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COVID-19 vaccine efficacy has been evaluated in large clinical trials and in real-world situation. Although they have proven to be very effective in the general population, little is known about their efficacy in immunocompromised patients. HIV-infected individuals’ response to vaccine may vary according to the type of vaccine and their level of immunosuppression. We evaluated immunogenicity of an mRNA anti-SARS CoV-2 vaccine in HIV-positive individuals. HIV-positive individuals (n = 121) were recruited from HIV clinics in Montreal and stratified according to their CD4 counts. A control group of 20 health care workers naïve to SARS CoV-2 was used. The participants’ Anti-RBD IgG responses were measured by ELISA at baseline and 3–4 weeks after receiving the first dose of an mRNA vaccine). Eleven of 121 participants had anti-COVID-19 antibodies at baseline, and a further 4 had incomplete data for the analysis. Mean anti-RBD IgG responses were similar between the HIV negative control group (n = 20) and the combined HIV+ group (n = 106) (p = 0.72). However, these responses were significantly lower in the group with <250 CD4 cells/mm3. (p < 0.0001). Increasing age was independently associated with decreased immunogenicity. HIV-positive individuals with CD4 counts over 250 cells/mm3 have an anti-RBD IgG response similar to the general population. However, HIV-positive individuals with the lowest CD4 counts (<250 cells/mm3) have a weaker response. These data would support the hypothesis that a booster dose might be needed in this subgroup of HIV-positive individuals, depending on their response to the second dose.

IntroductionAVT05, a recombinant human IgG1қ monoclonal antibody (mAb), is a proposed biosimilar to golimumab. The purpose of this study was to investigate the pharmacokinetic (PK) similarity, safety, tolerability, and immunogenicity between AVT05 and US-licensed and EU-approved reference product (RP) golimumab (US-RP and EU-RP, respectively) in healthy adult participants.Methods336 healthy male and female participants aged 18 to 55 years were randomized in a 1:1:1 ratio to AVT05, US-RP or EU-RP (figure 1). Participants received a single 50 mg/0.5 mL subcutaneous injection on Day 1 and were followed until Day 75. The primary PK endpoints were maximum serum concentration (Cmax) and area under the serum concentration-time curve from time zero to infinity (AUC0-inf). PK similarity is demonstrated if the 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for both AUC0-inf and Cmax contained entirely within the prespecified margins of 80.00% and 125.00% for all six pairwise treatment comparisons (figure 1). Secondary endpoints were additional PK parameters (AUC0-t, Tmax, Kel, t1/2, Vz/F, and CL/F), safety, tolerability and immunogenicity.ResultsDemographic and baseline characteristics were balanced between the treatment groups. The 90% CI for GMR of both primary PK parameters (AUC0-inf and Cmax) for all three pairwise comparisons was within the prespecified margins of 80.00% and 125.00%. The secondary PK parameters were also comparable among the treatment arms. The mean serum golimumab concentrations through Day 75 post-dose were similar between treatment arms.Overall, 66.1% of participants experienced at least one treatment-emergent adverse event (TEAE) during the study period. The frequency of TEAEs was comparable among the treatment arms. Majority of the TEAEs were mild to moderate in severity. There were 2 serious TEAEs reported (1(0.9%) each in AVT05 and EU-RP arms), neither of which were considered treatment-related. Local administration site reactions were mild in severity and observed in 6.1%, 10.8% and 5.5% of participants in the AVT05, EU-RP and US-RP arms, respectively. Overall, 87 (75.7%), 92 (82.9%) and 89 (80.9%) participants in the AVT05, EU-RP and US-RP arms, respectively, were anti-drug antibodies (ADAs) positive, among those 66 (57.4%), 68 (61.3%) and 61 (55.5%) participants, respectively, were neutralizing antibodies (NAbs) positive at least once during the study. The primary PK parameters (AUC0-inf and Cmax) were slightly lower in ADA positive participants compared to ADA negative ones.Abstract P266 Figure 1Study schematic for AVT05-GL-P01[Figure omitted. See PDF]ConclusionsFollowing a single dose administration, the study supported a demonstration of pharmacokinetic similarity between AVT05 and EU-and US-RP in healthy participants. Safety, tolerability, and immunogenicity profiles were comparable between the treatment arms.

Bringing safe and effective drugs to patients is of utmost importance for the pharmaceutical industry, with immunogenicity (IG) being a critical factor that influences both aspects. Biotherapeutics can elicit unwanted immune responses, potentially leading to (severe) safety implications, reduced patient benefits, and may result in termination of development. Therefore, understanding IG risks throughout drug development is essential for both drug developers and health agencies (HAs). The Immunogenicity Risk Assessment (IRA) facilitates the identification of IG risk factors and allows the establishment of effective mitigation and monitoring strategies. In this publication, the European Immunogenicity Platform (EIP) presents a comprehensive IRA framework aligned across pharmaceutical industry, emphasizing its significance in product development - from early de-risking to bioanalytical monitoring and mitigation measures during clinical trials. The EIP also provides an updated list of IG risks, offers distinct recommendations for assigning overall IG risk levels prior to the start of clinical development and highlights business considerations within this assessment.

Some recent reports have already highlighted the risk of SARS-CoV-2 infection in patients treated with RTX.1–4 Besides the risk of a more severe disease course during B cell depleting therapy, a major concern relates to a risk of reduced immunogenicity of vaccination. [...]the question arises if patients should withhold or interrupt RTX therapy around COVID-19 vaccination or delay vaccination. To determine a SARS-CoV-2 specific T cell reactivity, we measured interferon (IFN)-γ response to SARS-CoV-2 peptides in our patient cohort and control groups. After stimulation with two different SARS-CoV-2 specific antigen mixes, IFN-γ response could be detected in the vaccinated healthy control group as well as in the patient cohort, independent of the humoral immune response (online supplemental figure S2).

SARS-CoV-2 mRNA vaccination elicited high immunogenicity in immunocompetent people in the original vaccine trials,1 2 though recent studies have shown blunted immunogenicity in patients with rheumatic and musculoskeletal diseases (RMDs) after a single dose and case reports of non-response after two doses.3 4 We previously detailed antibody response in patients with RMD following the first dose of SARS-CoV-2 mRNA vaccination and herein report response and factors associated with response to two-dose vaccination in a larger cohort. Despite a blunted humoral response in participants on these regimens, the rate of seroconversion was comparable with those seen in the original vaccine trials and existing studies on patients with RMD.1 2 6 Limitations of this study include a younger, generally female, racially homogenous population and limited information on immunomodulatory timing and dosage. Disclaimer The analyses described here are the responsibility of the authors alone and do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organisations imply endorsement by the US Government.

Biological molecules are increasingly becoming a part of the therapeutics portfolio that has been either recently approved for marketing or those that are in the pipeline of several biotech and pharmaceutical companies. This is largely based on their ability to be highly specific relative to small molecules. However, by virtue of being a large protein, and having a complex structure with structural variability arising from production using recombinant gene technology in cell lines, such therapeutics run the risk of being recognized as foreign by a host immune system. In the context of immune-mediated adverse effects that have been documented to biological drugs thus far, including infusion reactions, and the evolving therapeutic platforms in the pipeline that engineer different functional modules in a biotherapeutic, it is critical to understand the interplay of the adaptive and innate immune responses, the pathophysiology of immunogenicity to biological drugs in instances where there have been immune-mediated adverse clinical sequelae and address technical approaches for their laboratory evaluation. The current paradigm in immunogenicity evaluation has a tiered approach to the detection and characterization of anti-drug antibodies (ADAs) elicited in vivo to a biotherapeutic; alongside with the structural, biophysical, and molecular information of the therapeutic, these analytical assessments form the core of the immunogenicity risk assessment. However, many of the immune-mediated adverse effects attributed to ADAs require the formation of a drug/ADA immune complex (IC) intermediate that can have a variety of downstream effects. This review will focus on the activation of potential immunopathological pathways arising as a consequence of circulating as well as cell surface bound drug bearing ICs, risk factors that are intrinsic either to the therapeutic molecule or to the host that might predispose to IC-mediated effects, and review the recent literature on prevalence and intensity of established examples of type II and III hypersensitivity reactions that follow the administration of a biotherapeutic. Additionally, we propose methods for the study of immune parameters specific to the biology of ICs that could be of use in conjunction with the detection of ADAs in circulation.

Malaria is a leading cause of morbidity and mortality worldwide. We previously reported the efficacy of the R21/Matrix-M malaria vaccine, which reached the WHO-specified goal of 75% or greater efficacy over 12 months in the target population of African children. Here, we report the safety, immunogenicity, and efficacy results at 12 months following administration of a booster vaccination. This double-blind phase 1/2b randomised controlled trial was done in children aged 5–17 months in Nanoro, Burkina Faso. Eligible children were enrolled and randomly assigned (1:1:1) to receive three vaccinations of either 5 μg R21/25 μg Matrix-M, 5 μg R21/50 μg Matrix-M, or a control vaccine (the Rabivax-S rabies vaccine) before the malaria season, with a booster dose 12 months later. Children were eligible for inclusion if written informed consent could be provided by a parent or guardian. Exclusion criteria included any existing clinically significant comorbidity or receipt of other investigational products. A random allocation list was generated by an independent statistician by use of block randomisation with variable block sizes. A research assistant from the University of Oxford, independent of the trial team, prepared sealed envelopes using this list, which was then provided to the study pharmacists to assign participants. All vaccines were prepared by the study pharmacists by use of the same type of syringe, and the contents were covered with an opaque label. Vaccine safety, efficacy, and a potential correlate of efficacy with immunogenicity, measured as anti-NANP antibody titres, were evaluated over 1 year following the first booster vaccination. The population in which the efficacy analyses were done comprised all participants who received the primary series of vaccinations and a booster vaccination. Participants were excluded from the efficacy analysis if they withdrew from the trial within the first 2 weeks of receiving the booster vaccine. This trial is registered with ClinicalTrials.gov (NCT03896724), and is continuing for a further 2 years to assess both the potential value of additional booster vaccine doses and longer-term safety. Between June 2, and July 2, 2020, 409 children returned to receive a booster vaccine. Each child received the same vaccination for the booster as they received in the primary series of vaccinations; 132 participants received 5 μg R21 adjuvanted with 25 μg Matrix-M, 137 received 5 μg R21 adjuvanted with 50 μg Matrix-M, and 140 received the control vaccine. R21/Matrix-M had a favourable safety profile and was well tolerated. Vaccine efficacy remained high in the high adjuvant dose (50 μg) group, similar to previous findings at 1 year after the primary series of vaccinations. Following the booster vaccination, 67 (51%) of 132 children who received R21/Matrix-M with low-dose adjuvant, 54 (39%) of 137 children who received R21/Matrix-M with high-dose adjuvant, and 121 (86%) of 140 children who received the rabies vaccine developed clinical malaria by 12 months. Vaccine efficacy was 71% (95% CI 60 to 78) in the low-dose adjuvant group and 80% (72 to 85) in the high-dose adjuvant group. In the high-dose adjuvant group, vaccine efficacy against multiple episodes of malaria was 78% (95% CI 71 to 83), and 2285 (95% CI 1911 to 2568) cases of malaria were averted per 1000 child-years at risk among vaccinated children in the second year of follow-up. Among these participants, at 28 days following their last R21/Matrix-M vaccination, titres of malaria-specific anti-NANP antibodies correlated positively with protection against malaria in both the first year of follow-up (Spearman's ρ –0·32 [95% CI –0·45 to –0·19]; p=0·0001) and second year of follow-up (–0·20 [–0·34 to –0·06]; p=0·02). A booster dose of R21/Matrix-M at 1 year following the primary three-dose regimen maintained high efficacy against first and multiple episodes of clinical malaria. Furthermore, the booster vaccine induced antibody concentrations that correlated with vaccine efficacy. The trial is ongoing to assess long-term follow-up of these participants and the value of further booster vaccinations. European and Developing Countries Clinical Trials Partnership 2 (EDCTP2), Wellcome Trust, and NIHR Oxford Biomedical Research Centre. For the French translation of the abstract see Supplementary Materials section.

In a phase 3 trial involving more than 15,000 participants, two doses of NVX-CoV2373, a recombinant SARS-CoV-2 nanoparticle vaccine, administered 21 days apart had a vaccine efficacy of 89.7%. Reactogenicity was generally mild and transient, and adverse events were infrequent and of low grade.

Inhibitors of DNA methyltransferases and of histone deacetylases induce transcription from cryptic transposable elements, which results in 5′-truncated and mis-spliced proteins that may increase cancer immunogenicity.