Efficacy and safety of tixagevimab/cilgavimab as passive immunisation against COVID-19 infections in patients with hematological malignancies.

Monoclonal antibodies, as tixagevimab/cilgavimab, have been introduced as prophylaxis against COVID-19 infections in high-risk populations. However, data on efficacy are limited. This study investigates efficacy and tolerability of tixagevimab/cilgavimab in hematological patients under real-life conditions. Tixagevimab/cilgavimab was administered to 155 hematological patients (March-August 2022) at two Austrian centres. S/RBD-antibody assessments were performed before (T0), four weeks (T1), and six months (T2) after application. Side effects, the occurrence of COVID-19 infections, and the course of S/RBD-antibody titres were analysed retrospectively in relation to clinical variables. 155 hematological patients, who refused tixagevimab/cilgavimab, were included as a control group to compare the frequency of COVID-19 infections. Of all immunised patients (52.3% males; 91% triple vaccinated), 25.8% had a COVID-19 breakthrough infection (76% mild) compared to 43.9% in the control group. Patients with chronic lymphocytic leukaemia (CLL)/lymphoma were at highest risk of a COVID-19 infection (OR = 2.21; 95% CI 1.05-4.65; p = 0.037). After immunisation, a steep increase in median antibody levels (1193.4BAU/ml, IQR 0-2318.94) was observed in 67.8%, followed by a rapid decrease between T1 and T2 (465.95BAU/ml, IQR 0-1900.65.3) with the greatest declines in CLL/lymphoma (848.7BAU/ml, IQR 0-1949.6, p = 0.026). Side-effects occurred in 21.2% (CTCAE I/II). These real-world data indicate that S/RBD antibodies respond rapidly after passive immunisation in all hematological patients without safety concerns. Given the rapid decline in S/RBD antibodies, early booster immunisations should be considered for future scenarios in this vulnerable group.

Convalescent plasma for COVID-19: a meta-analysis, trial sequential analysis, and meta-regression.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies, particularly those preventing interaction between the viral spike receptor-binding domain and the host angiotensin-converting enzyme 2 receptor, may prevent viral entry into host cells and disease progression. METHODS: We performed a systematic review, meta-analysis, trial sequential analysis (TSA), and meta-regression of RCTs to evaluate the benefit of convalescent plasma for COVID-19. The primary outcome was 28-30 day mortality. Secondary outcomes included need for mechanical ventilation and ICU admission. Data sources were PubMed, Embase, MedRxiv, and the Cochrane library on July 2, 2021. RESULTS: We identified 17 RCTs that recruited 15 587 patients with 8027 (51.5%) allocated to receive convalescent plasma. Convalescent plasma use was not associated with a mortality benefit (24.7% vs 25.5%; odds ratio [OR]=0.94 [0.85-1.04]; P=0.23; I2=4%; TSA adjusted confidence interval [CI], 0.84-1.05), or reduction in need for mechanical ventilation (15.7% vs 15.4%; OR=1.01 [0.92-1.11]; P=0.82; I2=0%; TSA adjusted CI, 0.91-1.13), or ICU admission (22.4% vs 16.7%; OR=0.80 [0.21-3.09]; P=0.75; I2=63%; TSA adjusted CI, 0.0-196.05). Meta-regression did not reveal association with titre of convalescent plasma, timing of administration, or risk of death and treatment effect (P>0.05). Risk of bias was high in most studies. CONCLUSIONS: In patients with COVID-19, there was no clear mortality benefit associated with convalescent plasma treatment. In patients with mild disease, convalescent plasma did not prevent either the need for mechanical ventilation or ICU admission. CLINICAL TRIAL REGISTRATION: CRD42021234201 (PROSPERO).

Persistent SARS-CoV-2 infection in patients with secondary antibody deficiency: successful clearance following combination casirivimab and imdevimab (REGN-COV2) monoclonal antibody therapy.

BACKGROUND: There is growing evidence that antibody responses play a role in the resolution of SARS-CoV-2 infection. Patients with primary or secondary antibody deficiency are at increased risk of persistent infection. This challenging clinical scenario is associated with adverse patient outcome and potentially creates an ecological niche for the evolution of novel SARS-CoV-2 variants with immune evasion capacity. Case reports and/or series have implied a therapeutic role for convalescent plasma (CP) to secure virological clearance, although concerns have been raised about the effectiveness of CP and its potential to drive viral evolution, and it has largely been withdrawn from clinical use in the UK. CASE PRESENTATION: We report two cases in which persistent SARS-CoV-2 infection was cleared following administration of the monoclonal antibody combination casirivimab and imdevimab (REGN-COV2, Ronapreve). A 55-year-old male with follicular lymphoma, treated with B cell depleting therapy, developed SARS-CoV-2 infection in September 2020 which then persisted for over 200 days. He was hospitalised on four occasions with COVID-19 and suffered debilitating fatigue and malaise throughout. There was no clinical response to antiviral therapy with remdesivir or CP, and SARS-CoV-2 was consistently detected in nasopharyngeal swabs. Intrahost evolution of several spike variants of uncertain significance was identified by viral sequence analysis. Delivery of REGN-COV2, in combination with remdesivir, was associated with clinical improvement and viral clearance within 6 days, which was sustained for over 150 days despite immunotherapy for relapsed follicular lymphoma. The second case, a 68-year-old female with chronic lymphocytic leukaemia on ibrutinib, also developed persistent SARS-CoV-2 infection. Despite a lack of response to remdesivir, infection promptly cleared following REGN-COV2 in combination with remdesivir, accompanied by resolution of inflammation and full clinical recovery that has been maintained for over 290 days. CONCLUSIONS: These cases highlight the potential benefit of REGN-COV2 as therapy for persistent SARS-CoV-2 infection in antibody deficient individuals, including after failure of CP treatment. Formal clinical studies are warranted to assess the effectiveness of REGN-COV2 in antibody-deficient patients, especially in light of the emergence of variants of concern, such as Omicron, that appear to evade REGN-COV2 neutralisation.

Recent advances in tau-directed immunotherapy against Alzheimer's disease: an overview of pre-clinical and clinical development.

Alzheimer's disease (AD) has been a worldwide concern for many years now. This is due to the fact that AD is an irreversible and progressive neurodegenerative disease that affects quality of life. Failure of some Phase II/III clinical trials in AD targeting accumulation of ß-amyloid in the brain has led to an increase in interest in studying alternative treatments against tubulin-associated unit (Tau) pathology. These alternative treatments include active and passive immunisation. Based on numerous studies, Tau is reported as a potential immunotherapeutic target for tauopathy-related diseases including AD. Accumulation and aggregation of hyperphosphorylated Tau as neuropil threads and neurofibrillary tangles (NFT) are pathological hallmarks of AD. Both active and passive immunisation targeting Tau protein have shown the capabilities to decrease or prevent Tau pathology and improve either motor or cognitive impairment in various animal models. In this review, we summarise recent advances in active and passive immunisation targeting pathological Tau protein, and will discuss with data obtained from both animal and human trials. Together, we give a brief overview about problems being encountered in these immunotherapies.

Evidence for the role of INSL3 on sperm production in boars by passive immunisation.

Insulin-like factor 3 (INSL3), previously called relaxin-like factor, is essential for foetal testis descent and has been implicated in sperm production in adult males. This study investigated the role of INSL3 in sperm production by examining the effect of neutralising INSL3 by passive immunisation on testicular function and sperm output in boars. Six male Duroc boars were randomly assigned to passive immunisation and control groups (n = 3 each). The immunisation group was intravenously injected with an IgG fraction of anti-INSL3 antibody developed against the B domain of INSL3 at 2-week intervals from 21-40 weeks of age. The control group was treated with normal IgG in the same manner. Antibody administration reduced testis weight and caused a fourfold increase in the frequency of apoptotic germ cells, which was associated with upregulation of the pro-apoptotic caspase 3 and BAX, and downregulation of the anti-apoptotic XIAP and BCL2, and a substantial marked reduction in sperm concentration. Neutralising INSL3 delivered by passive immunisation reduced testis weight and sperm concentration by inducing germ cell apoptosis, suggesting that INSL3 acts as a germ cell survival/anti-apoptotic factor in the maintenance of sperm production.

Exploring the Role of Antiviral Nasal Sprays in the Control of Emerging Respiratory Infections in the Community.

INTRODUCTION: The COVID-19 pandemic has demonstrated that there is an unmet need for the development of novel prophylactic antiviral treatments to control the outbreak of emerging respiratory virus infections. Passive antibody-based immunisation approaches such as intranasal antibody prophylaxis have the potential to provide immediately accessible universal protection as they act directly at the most common route of viral entry, the upper respiratory tract. The need for such products is very apparent for SARS-CoV-2 at present, given the relatively low effectiveness of vaccines to prevent infection and block virus onward transmission. We explore the benefits and challenges of the use of antibody-based nasal sprays prior and post exposure to the virus. METHODS: The classic susceptible-exposed-infectious-removed (SEIR) mathematical model was extended to describe the potential population-level impact of intranasal antibody prophylaxis on controlling the spread of an emerging respiratory infection in the community. RESULTS: Intranasal administration of monoclonal antibodies provides only a short-term protection to the mucosal surface. Consequently, sustained intranasal antibody prophylaxis of a substantial proportion of the population would be needed to contain infections. Post-exposure prophylaxis against the development of severe disease would be essential for the overall reduction in hospital admissions. CONCLUSION: Antibody-based nasal sprays could provide protection against infection to individuals that are likely to be exposed to the virus. Large-scale administration for a long period of time would be challenging. Intranasal antibody prophylaxis alone cannot prevent community-wide transmission of the virus. It could be used along with other protective measures, such as non-pharmaceutical interventions, to bridge the time required to develop and produce effective vaccines, and complement active immunisation strategies.

Prognostic and therapeutic considerations of antibodies against c-ter apolipoprotein A-1 in the general population.

OBJECTIVES: Autoantibodies against apolipoprotein A1 (anti-apoA1 IgGs) and its C-terminal region (cter apoA1) have emerged as an independent biomarker for cardiovascular disease. Cter apoA1 mimetic peptides were shown to reverse the deleterious anti-apoA1 IgG effects in vitro. We evaluated the association of anti-cter apoA1 IgGs with overall mortality in the general population and tested the ability of a cter apoA1 mimetic peptide to reverse the anti-apoA1 IgG-induced inflammatory response and mortality in vitro and in vivo, respectively. METHODS: Anti-cter apoA1 IgGs were measured in serum samples of 6386 participants of the CoLaus study of which 5220 were followed for a median duration of 5.6 years. The primary outcome was overall mortality. The peptide inhibitory concentration 50% (IC50) was determined in vitro on HEK-Blue-4 and RAW cells. ApoE-/- mice were exposed to 16 weeks of anti-apoA1IgG passive immunisation with and without peptide co-incubation. RESULTS: Anti-cter apoA1 IgGs were associated with higher interleukin 6 levels and independently predicted overall mortality; an increase of one standard deviation of anti-cter apoA1 IgG level was associated with an 18% increase in mortality risk (hazard ratio: 1.18, 95% confidence interval: 1.04-1.33; P = 0.009). The cterApoA1 analogue reversed the antibody-mediated inflammatory response with an IC50 of 1 µm in vitro but did not rescue the significant anti-apoA1 IgG-induced mortality rate in vivo (69% vs. 23%, LogRank P = 0.02). CONCLUSION: Anti-cter apoA1 IgG independently predicts overall mortality in the general population. Despite being effective in vitro, our cter apoA1 analogue did not reverse the anti-apoA1 IgG-induced mortality in mice. Our data suggest that these autoantibodies are not readily treatable through cognate peptide immunomodulation.

Engineered Recombinant Single Chain Variable Fragment of Monoclonal Antibody Provides Protection to Chickens Infected with H9N2 Avian Influenza.

Passive immunisation with neutralising antibodies can be a potent therapeutic strategy if used pre- or post-exposure to a variety of pathogens. Herein, we investigated whether recombinant monoclonal antibodies (mAbs) could be used to protect chickens against avian influenza. Avian influenza viruses impose a significant economic burden on the poultry industry and pose a zoonotic infection risk for public health worldwide. Traditional control measures including vaccination do not provide rapid protection from disease, highlighting the need for alternative disease mitigation measures. In this study, previously generated neutralizing anti-H9N2 virus monoclonal antibodies were converted to single-chain variable fragment antibodies (scFvs). These recombinant scFv antibodies were produced in insect cell cultures and the preparations retained neutralization capacity against an H9N2 virus in vitro. To evaluate recombinant scFv antibody efficacy in vivo, chickens were passively immunized with scFvs one day before, and for seven days after virus challenge. Groups receiving scFv treatment showed partial virus load reductions measured by plaque assays and decreased disease manifestation. These results indicate that antibody therapy could reduce clinical disease and shedding of avian influenza virus in infected chicken flocks.

The use of normal human immunoglobulin (NHIG) for public health purposes in Queensland 2004-2014 and Australia 2014-2016

Objective To describe the use of normal human immunoglobulin (NHIG) recommended for public health purposes in Queensland and Australia. Methods Queensland public health unit (PHU) data on notified cases of measles, rubella and hepatitis A from 2004 to 2014 were examined; particularly regarding the number of contacts offered NHIG and the volume recommended per contact. The National Blood Authority (NBA) provided unidentified data from NHIG order form inception (June 2014) through December 2016. Queensland orders were compared to PHU data where the data timeframes overlapped. Results NHIG usage varied by condition. For hepatitis A, usage declined after the introduction of vaccination for contacts in 2010. Usage fluctuated across the study period for measles and was not recommended for rubella. Average volumes per contact for hepatitis A and measles were 1.6mL and 11.9mL respectively based on PHU data. PHU data approximated NBA data on NHIG usage for hepatitis A and rubella contacts. Calculated volumes of NHIG per measles contact were also similar, but PHU data underestimated the number of measles contacts for whom NHIG was ordered. Discussion This study is the first to document the use of NHIG for public health purposes in Australia. Results will be valuable for national blood sufficiency planning and cost effectiveness studies in the event of alterations to NHIG dosage recommendations.

Passive immunisation, an old idea revisited: Basic principles and application to modern animal production systems.

Immunisation by administration of antibodies (immunoglobulins) has been known for more than one hundred years as a very efficient means of obtaining immediate, short-lived protection against infection and/or against the disease-causing effects of toxins from microbial pathogens and from other sources. Thus, due to its rapid action, passive immunisation is often used to treat disease caused by infection and/or toxin exposure. However immunoglobulins may also be administered prior to exposure to infection and/or toxin, although they will not provide long-lasting protection as is seen with active immunisation (vaccination) in which an immunological memory is established by controlled exposure of the host to the pathogen in question. With multi-factorial infectious diseases in production animals, especially those that have proven hard to control by vaccination, the potential of passive immunisation remains big. This review highlights a number of examples on the use of passive immunisation for the control of infectious disease in the modern production of a range of animals, including pigs, cattle, sheep, goat, poultry and fish. Special emphasis is given on the enablement of passive immunisation strategies in these production systems through low cost and ease of use as well as on the sources, composition and purity of immunoglobulin preparations used and their benefits as compared to current measures, including vaccination (also comprising maternal vaccination), antibiotics and feed additives such as spray-dried plasma. It is concluded that provided highly efficient, relatively low-price immunoglobulin products are available, passive immunisation has a clear role in the modern animal production sector as a means of controlling infectious diseases, importantly with a very low risk of causing development of bacterial resistance, thus constituting a real and widely applicable alternative to antibiotics.

Antiserum from mice vaccinated with modified vaccinia Ankara virus expressing African horse sickness virus (AHSV) VP2 provides protection when it is administered 48h before, or 48h after challenge.

Previous studies show that a recombinant modified vaccinia Ankara (MVA) virus expressing VP2 of AHSV serotype 4 (MVA-VP2) induced virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR -/-) against challenge. Follow up experiments indicated that passive transfer of antiserum, from MVA-VP2 immune donors to recipient mice 1h before challenge, conferred complete clinical protection and significantly reduced viraemia. These studies have been extended to determine the protective effect of MVA-VP2 vaccine-induced antiserum, when administered 48h before, or 48h after challenge. In addition, passive transfer of splenocytes was undertaken to assess if they confer any degree of immunity to immunologically naïve recipient mice. Thus, antisera and splenocytes were collected from groups of mice that had been vaccinated with MVA-VP2, or wild type MVA (MVA-wt), for passive immunisation of recipient mice. The latter were subsequently challenged with AHSV-4 (together with appropriate vaccinated or unvaccinated control animals) and protection was assessed by comparing clinical signs, lethality and viraemia between treated and control groups. All antiserum recipients showed high protection against disease (100% survival rates even in mice that were immunised 48h after challenge) and statistically significant reduction or viraemia in comparison with the control groups. The mouse group receiving splenocytes from MVA-VP2 vaccinates, showed only a 40% survival rate, with a small reduction in viraemia, compared to those mice that had received splenocytes from MVA-wt vaccinates. These results confirm the primarily humoral nature of protective immunity conferred by MVA-VP2 vaccination and show the potential of administering MVA-VP2 specific antiserum as an emergency treatment for AHSV.

Vaccination of mice with a modified Vaccinia Ankara (MVA) virus expressing the African horse sickness virus (AHSV) capsid protein VP2 induces virus neutralising antibodies that confer protection against AHSV upon passive immunisation.

In previous studies we showed that a recombinant Modified Vaccinia Ankara (MVA) virus expressing the protein VP2 of AHSV serotype 4 (MVA-VP2) induced virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR-/-) against challenge. We continued these studies and determined, in the IFNAR-/- mouse model, whether the antibody responses induced by MVA-VP2 vaccination play a key role in protection against AHSV. Thus, groups of mice were vaccinated with wild type MVA (MVA-wt) or MVA-VP2 and the antisera from these mice were used in a passive immunisation experiment. Donor antisera from (a) MVA-wt; (b) MVA-VP2 vaccinated; or (c) MVA-VP2 vaccinated and AHSV infected mice, were transferred to AHSV non-immune recipient mice. The recipients were challenged with virulent AHSV together with MVA-VP2 vaccinated and MVA-wt vaccinated control animals and the levels of protection against AHSV-4 were compared between all these groups. The results showed that following AHSV challenge, mice that were passively immunised with MVA-VP2 vaccinated antisera were highly protected against AHSV disease and had lower levels of viraemia than recipients of MVA-wt antisera. Our study indicates that MVA-VP2 vaccination induces a highly protective humoral immune response against AHSV.