Host-directed immunotherapy to fight infectious diseases.

PURPOSE OF REVIEW: This review provides readers with examples of refractory infections due to inborn errors of immunity, highlighting how they may be successfully treated by deducing and targeting the underlying immunodeficiency. RECENT FINDINGS: The use of host-directed immunotherapy to treat infectious disease in inborn errors of immunity is currently limited but growing. Different strategies include depleting the cellular reservoir for pathogens with restricted cell-tropism; augmenting the diminished effector response; and restoring molecular equipoise. The immunotherapies illustrated are existing drugs that have been re-purposed and rationally used, depending on the molecular or cellular impact of the mutation. As more biologic response modifiers and molecular targeted therapies are developed for other indications, they open the avenues for their use in inborn errors of immunity. Conversely, as more molecular pathways underlying defective immune responses and refractory infections are elucidated, they lend themselves to tractability with these emerging therapies. SUMMARY: Infections that fail appropriate antimicrobial therapy are a harbinger of underlying inborn errors of immunity. Dissecting the mechanism by which the immune system fails provides opportunities to target the host response and make it succeed.

Real-world serological responses to extended-interval and heterologous COVID-19 mRNA vaccination in frail, older people (UNCoVER): an interim report from a prospective observational cohort study.

BACKGROUND: The use of COVID-19 vaccines has been prioritised to protect the most vulnerable-notably, older people. Because of fluctuations in vaccine availability, strategies such as delayed second dose and heterologous prime-boost have been used. However, the effectiveness of these strategies in frail, older people are unknown. We aimed to assess the antigenicity of mRNA-based COVID-19 vaccines in frail, older people in a real-world setting, with a rationed interval dosing of 16 weeks between the prime and boost doses. METHODS: This prospective observational cohort study was done across 12 long-term care facilities of the Montréal Centre-Sud - Integrated University Health and Social Services Centre in Montréal, Québec, Canada. Under a rationing strategy mandated by the provincial government, adults aged 65 years and older residing in long-term care facilities in Québec, Canada, with or without previously documented SARS-CoV-2 infection, were administered homologous or heterologous mRNA vaccines, with an extended 16-week interval between doses. All older residents in participating long-term care facilities who received two vaccine doses were eligible for inclusion in this study. Participants were enrolled from Dec 31, 2020, to Feb 16, 2021, and data were collected up to June 9, 2021. Clinical data and blood samples were serially collected from participants at the following timepoints: at baseline, before the first dose; 4 weeks after the first dose; 6-10 weeks after the first dose; 16 weeks after the first dose, up to 2 days before administration of the second dose; and 4 weeks after the second dose. Sera were tested for SARS-CoV-2-specific IgG antibodies (to the trimeric spike protein, the receptor-binding domain [RBD] of the spike protein, and the nucleocapsid protein) by automated chemiluminescent ELISA. Two cohorts were used in this study: a discovery cohort, for which blood samples were collected before administration of the first vaccine dose and longitudinally thereafter; and a confirmatory cohort, for which blood samples were only collected from 4 weeks after the prime dose. Analyses were done in the discovery cohort, with validation in the confirmatory cohort, when applicable. FINDINGS: The total study sample consisted of 185 participants. 65 participants received two doses of mRNA-1273 (Spikevax; Moderna), 36 received two doses of BNT162b2 (Comirnaty; Pfizer-BioNTech), and 84 received mRNA-1273 followed by BNT162b2. In the discovery cohort, after a significant increase in anti-RBD and anti-spike IgG concentrations 4 weeks after the prime dose (from 4·86 log binding antibody units [BAU]/mL to 8·53 log BAU/mL for anti-RBD IgG and from 5·21 log BAU/mL to 8·05 log BAU/mL for anti-spike IgG), there was a significant decline in anti-RBD and anti-spike IgG concentrations until the boost dose (7·10 log BAU/mL for anti-RBD IgG and 7·60 log BAU/mL for anti-spike IgG), followed by an increase 4 weeks later for both vaccines (9·58 log BAU/mL for anti-RBD IgG and 9·23 log BAU/mL for anti-spike IgG). SARS-CoV-2-naive individuals showed lower antibody responses than previously infected individuals at all timepoints tested up to 16 weeks after the prime dose, but achieved similar antibody responses to previously infected participants by 4 weeks after the second dose. Individuals primed with the BNT162b2 vaccine showed a larger decrease in mean anti-RBD and anti-spike IgG concentrations with a 16-week interval between doses (from 8·12 log BAU/mL to 4·25 log BAU/mL for anti-RBD IgG responses and from 8·18 log BAU/mL to 6·66 log BAU/mL for anti-spike IgG responses) than did those who received the mRNA-1273 vaccine (two doses of mRNA-1273: from 8·06 log BAU/mL to 7·49 log BAU/mL for anti-RBD IgG responses and from 6·82 log BAU/mL to 7·56 log BAU/mL for anti-spike IgG responses; mRNA-1273 followed by BNT162b2: from 8·83 log BAU/mL to 7·95 log BAU/mL for anti-RBD IgG responses and from 8·50 log BAU/mL to 7·97 log BAU/mL for anti-spike IgG responses). No differences in antibody responses 4 weeks after the second dose were noted between the two vaccines, in either homologous or heterologous combinations. INTERPRETATION: Interim results of this ongoing longitudinal study show that among frail, older people, previous SARS-CoV-2 infection and the type of mRNA vaccine influenced antibody responses when used with a 16-week interval between doses. In these cohorts of frail, older individuals with a similar age and comorbidity distribution, we found that serological responses were similar and clinically equivalent between the discovery and confirmatory cohorts. Homologous and heterologous use of mRNA vaccines was not associated with significant differences in antibody responses 4 weeks following the second dose, supporting their interchangeability. FUNDING: Public Health Agency of Canada, Vaccine Surveillance Reference Group; and the COVID-19 Immunity Task Force. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Prefilled syringes for immunoglobulin G (IgG) replacement therapy: clinical experience from other disease settings.

INTRODUCTION: Ready-to-use prefilled syringes for drug delivery are increasingly used across a broad spectrum of clinical specialties. For patients with primary immunodeficiencies manifesting as antibody deficiencies, immunoglobulin G (IgG) replacement therapy (IgRT) by subcutaneous administration is an established treatment modality. Expanding IgRT administration options through the introduction of prefilled syringes may further improve its utility. AREAS COVERED: Here, we collate experience with prefilled syringes from other clinical settings to inform on their practicality and suitability for IgRT. In addition to discussing drug characteristics such as stability, pharmacokinetics, and efficacy, we focus on treatment delivery, physician/patient experience, costs, and the importance of education for the use of prefilled syringes. EXPERT OPINION: Perceived benefits of prefilled syringes include accurate dosing, sterility, and reduced treatment time, while offering patients greater choice, convenience, and ease-of-use. Our review of clinical experience with prefilled syringes supports this consensus. Relatively few studies directly compare prefilled syringes with conventional administration, and robust studies of cost-effectiveness and health-related quality of life are needed on a drug-by-drug basis. Growth in the availability of prefilled syringes will continue, encouraged by the importance of patient choice and treatment convenience, toward the goal of individualized treatment regimens and improved quality of life.