A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis.

Autosomal recessive tyrosine kinase 2 (TYK2) deficiency is characterized by susceptibility to mycobacterial and viral infections. Here, we report a 4-year-old female with severe respiratory viral infections, EBV-driven Burkitt-like lymphoma, and infection with the neurotropic Jamestown Canyon virus. A novel, homozygous c.745C > T (p.R249*) variant was found in TYK2. The deleterious effects of the TYK2 lesion were confirmed by immunoblotting; by evaluating functional responses to IFN-α/ß, IL-10, and IL-23; and by assessing its scaffolding effect on the cell surface expression of cytokine receptor subunits. The effects of the mutation could not be pharmacologically circumvented in vitro, suggesting that alternative modalities, such as hematopoietic stem cell transplantation or gene therapy, may be needed. We characterize the first patient from Canada with a novel homozygous mutation in TYK2.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 2: Inactivated Vaccines.

BACKGROUND AND AIMS: The effectiveness and safety of vaccinations can be altered by immunosuppressive therapies, and perhaps by inflammatory bowel disease (IBD) itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on inactivated vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative online platform, and voted on by a multidisciplinary group. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Consensus was reached on 15 of 20 questions. Recommendations address the following vaccines: Haemophilus influenzae type b, recombinant zoster, hepatitis B, influenza, pneumococcus, meningococcus, tetanus-diphtheria-pertussis, and human papillomavirus. Most of the recommendations for patients with IBD are congruent with the current Centers for Disease Control and Prevention and Canada's National Advisory Committee on Immunization recommendations for the general population, with the following exceptions. In patients with IBD, the panel suggested Haemophilus influenzae type b vaccine for patients older than 5 years of age, recombinant zoster vaccine for adults younger than 50 year of age, and hepatitis B vaccine for adults without a risk factor. Consensus was not reached, and recommendations were not made for 5 statements, due largely to lack of evidence, including double-dose hepatitis B vaccine, timing of influenza immunization in patients on biologics, pneumococcal and meningococcal vaccines in adult patients without risk factors, and human papillomavirus vaccine in patients aged 27-45 years. CONCLUSIONS: Patients with IBD may be at increased risk of some vaccine-preventable diseases. Therefore, maintaining appropriate vaccination status in these patients is critical to optimize patient outcomes. In general, IBD is not a contraindication to the use of inactivated vaccines, but immunosuppressive therapy may reduce vaccine responses.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 1: Live Vaccines.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) may be at increased risk of some vaccine-preventable diseases. The effectiveness and safety of vaccinations may be altered by immunosuppressive therapies or IBD itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on live vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative process and voted on by a multidisciplinary panel. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Three good practice statements included reviewing a patient's vaccination status at diagnosis and at regular intervals, giving appropriate vaccinations as soon as possible, and not delaying urgently needed immunosuppressive therapy to provide vaccinations. There are 4 recommendations on the use of live vaccines. Measles, mumps, rubella vaccine is recommended for both adult and pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). Varicella vaccine is recommended for pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). For adults, recommendations are conditionally in favor of varicella vaccine for those not on immunosuppressive therapy, and against for those on therapy. No recommendation was made regarding the use of live vaccines in infants born to mothers using biologics because the desirable and undesirable effects were closely balanced and the evidence was insufficient. CONCLUSIONS: Maintaining appropriate vaccination status in patients with IBD is critical to optimize patient outcomes. In general, live vaccines are recommended in patients not on immunosuppressive therapy, but not for those using immunosuppressive medications. Additional studies are needed to evaluate the safety and efficacy of live vaccines in patients on immunosuppressive therapy.

Revaccination and Adverse Event Recurrence in Patients with Adverse Events following Immunization.

OBJECTIVES: To estimate the risk of recurrence of adverse events following immunization (AEFIs) upon revaccination and to determine among patients with suspected vaccine allergy whether allergy skin test positivity was associated with AEFI recurrence. STUDY DESIGN: This prospective observational study included patients assessed in the Canadian Special Immunization Clinic Network from 2013 to 2019 with AEFIs who required revaccination with the vaccine temporally associated with their AEFI. Participants underwent standardized assessment and data collection. Special Immunization Clinic physicians used guidelines to inform their recommendations. Participants were followed up after revaccination to capture AEFI recurrences. Data were transferred to a central database for descriptive analysis. RESULTS: Overall, 588 participants were assessed for 627 AEFIs; 570 (91%) AEFIs occurred in children <18 years of age. AEFIs included immediate hypersensitivity (130/627; 21%), large local reactions (110/627; 18%), nonurticarial rash (51/627; 8%), seizures (26/627; 4%), and thrombocytopenia (11/627; 2%). Revaccination was recommended to 513 of 588 (87%) participants. Among participants recommended and due for revaccination during the study period, 63% (299/477) were revaccinated. AEFI recurrence was 10% (31/299) overall, 31% (15/49) for large local reactions, and 7% (5/66) for immediate hypersensitivity. No recurrence was serious. Among 92 participants with suspected vaccine allergy who underwent skin testing and were revaccinated, the negative predictive value of skin testing for AEFI recurrence was 96% (95% CI 92.5%-99.5%). CONCLUSIONS: Most individuals with AEFIs were safely revaccinated. Among those with suspected vaccine allergy, skin testing may help determine the safety of revaccination.

Cutaneous granulomas as the presenting manifestation of Griscelli syndrome type 2.

Griscelli syndrome type 2 is a rare autosomal recessive disorder characterized by hypopigmentation, silvery hair, and immunological dysfunction with no primary neurological impairment. We report an 18-month-old girl with Griscelli syndrome type 2 who presented to the dermatology department for cutaneous granulomas that developed following live-attenuated vaccination. Two compound heterozygous variants in the RAB27A gene were subsequently identified. She developed hemophagocytic lymphohistiocytosis, the key immunological concern, at age 5 years.

Uncommon clinical presentation of a common bug: Group A Streptococcus meningitis.

Group A Streptococcus (GAS) is a common pathogen in paediatric infections. However, it is a rare etiologic agent of bacterial meningitis. We describe a case of Streptococcus pyogenes meningitis complicated by sensorineural hearing loss in an immunocompetent 7-year-old boy. Clinicians should be aware of GAS as a potential cause of paediatric meningitis, especially with prominent symptoms suggestive of frontal sinusitis. Meningitis caused by GAS has been shown to be associated with significant mortality and morbidity, including neurological complications. Early screening for sensorineural hearing loss in patients with GAS meningitis can facilitate timely cochlear implant.

Waning Vaccine Immunity and Vaccination Responses in Children Treated for Acute Lymphoblastic Leukemia: A Canadian Immunization Research Network Study.

BACKGROUND: There is no uniform guideline for postchemotherapy vaccination of children with acute lymphoblastic leukemia (ALL). We evaluated waning immunity to 14 pneumococcal serotypes, pertussis toxin (PT), tetanus toxoid (TT) and varicella, and immunogenicity of postchemotherapy diphtheria, tetanus, pertussis, hepatitis B, polio, and Haemophilus influenzae type b (DTaP-IPV-Hib) and pneumococcal vaccination among previously vaccinated children treated for ALL. METHODS: This was a multicenter trial of children with ALL enrolled 4-12 months postchemotherapy completion. Exclusion criteria included: infant ALL, relapsed ALL, and stem cell transplant recipients. Immunocompetent children were recruited as controls. Postchemotherapy participants received DTaP-IPV-Hib and 13-valent pneumococcal conjugate vaccine (PCV13) concurrently, followed by 23-valent pneumococcal polysaccharide vaccine (PPV23) 2 months later. Serology was measured at baseline, 2 and 12 months postvaccination. Adverse events were captured via surveys. RESULTS: At enrollment, postchemotherapy participants (n = 74) were less likely than controls (n = 78) to be age-appropriately immunized with DTaP (41% vs 89%, P < .001) and PCV (59% vs 79%, P = .008). Geometric mean concentrations (GMCs) to TT, PT, PCV serotypes, and varicella were lower in postchemotherapy participants than controls after adjusting for previous vaccine doses (P < .001). Two months postvaccination, GMCs to TT, PT, and PCV serotypes increased from baseline (P < .001 for all antigens) and remained elevated at 12 months postvaccination. Antibody levels to PPV23 serotypes also increased postvaccination (P < .001). No serious adverse events were reported. CONCLUSIONS: Children treated for ALL had lower antibody levels than controls against pneumococcal serotypes, tetanus, pertussis, and varicella despite previous vaccination. Postchemotherapy vaccination with DTaP-IPV-Hib, PCV13, and PPV23 was immunogenic and well tolerated. Children with ALL would benefit from systematic revaccination postchemotherapy. CLINICAL TRIALS REGISTRATION: NCT02447718.

Live vaccines after pediatric solid organ transplant: Proceedings of a consensus meeting, 2018.

Growing evidence suggests receipt of live-attenuated viral vaccines after solid organ transplant (SOT) has occurred and is safe and needed due to lapses in herd immunity. A 2-day consortium of experts in infectious diseases, transplantation, vaccinology, and immunology was held with the objective to review evidence and create expert recommendations for clinicians when considering live viral vaccines post-SOT. For consideration of VV and MMR post-transplant, evidence exists only for kidney and liver transplant recipients. For MMR vaccine post-SOT, consider vaccination during outbreak or travel to endemic risk areas. Patients who have received antiproliferative agents (eg. mycophenolate mofetil), T cell-depleting agents, or rituximab; or have persistently elevated EBV viral loads, or are in a state of functional tolerance, should be vaccinated with caution and have a more in-depth evaluation to define benefit of vaccination and net state of immune suppression prior to considering vaccination. MMR and/or VV (not combined MMRV) is considered to be safe in patients who are clinically well, are greater than 1 year after liver or kidney transplant and 2 months after acute rejection episode, can be closely monitored, and meet specific criteria of "low-level" immune suppression as defined in the document.

Long-Term Outcome of Adenosine Deaminase-Deficient Patients-a Single-Center Experience.

PURPOSE: Inherited defects in the adenosine deaminase (ADA) enzyme can cause severe combined immune deficiency (SCID) and systemic abnormalities. Management options for ADA-deficient patients include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy (GT). Here, we describe the long-term benefits of these treatments. METHODS: Survival, infections, systemic sequelae, and laboratory assessments were recorded for all ADA-deficient SCID patients, managed at a single center since 1985, who survived 5 or more years following treatment. RESULTS: Of 20 ADA-deficient patients, the 8 (40%) who survived 5 or more years (range 6-29.5 years, median 14 years) were included in the study. Among the long-term survivors, two patients were treated exclusively with ERT, five underwent HSCT (three from HLA-matched sibling donors, two from HLA-mismatched related donors), and one received GT. The long-term survivors often suffered from recurrent respiratory infections; however, opportunistic infections occurred in only one patient. Systemic sequelae included lung disease such as bronchiectasis and asthma (four patients), neurologic abnormalities (six patients), metabolic disturbances (two patients), allergy and autoimmunity (six patients), and neoplasms (three patients). Normal CD4+ T cell numbers and function, as well as antibody production, were usually observed after HSCT and GT, but not after ERT. Late deaths occurred in two patients at 15 and 25 years after HSCT, respectively, and were attributed to respiratory failure. CONCLUSIONS: ADA-deficient patients commonly suffer from long-term complications, emphasizing the need for improved management and for multi-disciplinary follow-up.

Hybrid immunity after BNT162b2 Covid-19 vaccine administration in children aged 5 to 11 years.

BACKGROUND: The immune response to coronavirus disease 2019 (COVID-19) vaccination is stronger among adults with prior infection (hybrid immunity). It is important to understand if children demonstrate a similar response to better inform vaccination strategies. Our study investigated the humoral response after BNT162b2 COVID-19 vaccine doses in SARS-CoV-2 naïve and recovered children (5-11 years). METHODS: A multi-institutional, longitudinal, prospective cohort study was conducted. Children were enrolled in a case-ascertained antibody surveillance study in Ottawa, Ontario from September/2020-March/2021; at least one household member was severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positive on RT-PCR. In November 2021, BNT162b2 COVID-19 vaccine was authorized for children aged 5-11 in Canada. Children enrolled in the surveillance study intending to receive two vaccine doses were invited to participate in this study from November 2021-April 2022. Main exposure was prior SARS-CoV-2 infection, defined by positive RT-PCR or SARS-CoV-2 anti-N IgG antibody presence. Primary outcome was spike IgG antibody levels measured following the first vaccine dose (2-3 weeks) and second vaccine dose (3-4 weeks). RESULTS: Of the 153 eligible children, 75 participants (median age 8.9 IQR (7.4, 10.2) years; 38 (50.7 %) female; 59 (78.7 %) Caucasian) had complete follow-up. Fifty-four (72 %) children had prior SARS-COV-2 infection. Spike IgG antibody levels are significantly higher in SARS-CoV-2 recovered participants after receiving the first dose (p < 0.001) and the second (p = 0.01) compared to infection naïve children. CONCLUSIONS AND RELEVANCE: SARS-CoV-2 recovered children (5-11 years) demonstrated higher antibody levels following first BNT162b2 vaccine dose compared with naïve children. Most reached antibody saturation two to three weeks after the first dose; a second dose didn't change the saturation level. A single vaccine dose in SARS-CoV-2 recovered children may be equivalent or superior to a 2-dose primary series in naïve children. Further research is needed on the durability and quality of a single vaccine dose in this population.

Revaccination outcomes among adolescents and adults with suspected hypersensitivity reactions following COVID-19 vaccination: A Canadian immunization research network study.

BACKGROUND: COVID-19 vaccination has been associated with anaphylaxis and hypersensitivity reactions. Infectious disease physicians and allergists in the Canadian Special Immunization Clinic (SIC) Network developed guidance for evaluating patients with adverse events following immunization (AEFI) including suspected hypersensitivity. This study evaluated management and adverse event recurrence following subsequent COVID-19 vaccinations. METHODS: Individuals aged 12 years and older enrolled at participating SICs before February 28, 2023 who were referred for suspected or diagnosed hypersensitivity reaction following COVID-19 vaccination, or for prevaccination assessment of suspected allergy to a COVID-19 vaccine component were included. De-identified clinical assessments and revaccination data, captured in a centralized database, were analyzed. The Brighton Collaboration case definition (BCCD) for anaphylaxis (2023 version) was applied. RESULTS: The analysis included 206 participants from 13 sites: 26 participants referred for pre-vaccination assessment and 180 participants referred for adverse events following COVID-19 vaccination (15/180 [8.3%] with BCCD confirmed anaphylaxis, 84 [46.7%] with immediate hypersensitivity symptoms not meeting BCCD, 33 [18.3%] with other diagnosed hypersensitivity reactions, and 48 [26.7%] participants with a final diagnosis of non-hypersensitivity AEFI). Among participants referred for AEFIs following COVID-19 vaccination, 166/180 (92.2%) were recommended for COVID-19 revaccination after risk assessment, of whom 158/166 (95.2%) were revaccinated (all with a COVID-19 mRNA vaccine). After revaccination, 1/15 (6.7%) participants with prior anaphylaxis, 1/77 (1.3%) with immediate hypersensitivity not meeting criteria for anaphylaxis and 1/24 (4.2%) with other physician diagnosed hypersensitivity developed recurrent AEFI symptoms that met the BCCD for anaphylaxis. All 26 participants referred pre-vaccination, including 9 (34.6%) with history of polyethylene glycol-asparaginase reactions, were vaccinated without occurrence of immediate hypersensitivity symptoms. CONCLUSIONS: Most individuals in this national cohort who experienced a hypersensitivity event following COVID-19 vaccination and were referred for specialist review were revaccinated without AEFI recurrence, suggesting that specialist evaluation can facilitate safe revaccination.

A National Advisory Committee on Immunization (NACI) update on invasive meningococcal disease (IMD) epidemiology and program-relevant considerations for preventing IMD in individuals at high risk of exposure.

Following recent outbreaks of invasive meningococcal disease (IMD) in Canada and updates to provincial vaccination guidelines, the National Advisory Committee on Immunization (NACI) conducted a targeted review of evidence with a focus on immunization of adolescents and young adults. NACI reviewed national and international immunization recommendations for populations at high-risk of IMD, national IMD epidemiology and program-relevant considerations. Given the varied IMD epidemiology, NACI determined that recommending a pan-Canadian targeted program is currently challenging and that regional programs may be better suited to prevent IMD in population groups considered to be at high-risk of exposure. Further data is needed to ascertain contemporary risk factors for IMD (including activities and settings associated with bacterial acquisition, carriage and transmission) and estimate the true cost of meningococcal vaccine-preventable infections in Canada. To support provinces and territories in their decision-making, an outline of program-relevant elements for provincial and territorial consideration is provided.

Immunological effects and safety of live rotavirus vaccination after antenatal exposure to immunomodulatory biologic agents: a prospective cohort study from the Canadian Immunization Research Network.

BACKGROUND: People with inflammatory or autoimmune diseases are recommended to continue immunomodulatory biologic agents throughout pregnancy. However, concerns regarding potential immunosuppression in infants exposed to biologic agents have led to recommendations to avoid live vaccines in the first 6-12 months of life. We aimed to examine whether live rotavirus vaccine could be administered safely to infants exposed to biologic agents, assessed in the Canadian Special Immunization Clinic (SIC) Network. METHODS: In this prospective cohort study, infants exposed to biologic agents in utero were referred to one of six SIC sites in Canada for rotavirus vaccination recommendations. Children with other contraindications to rotavirus vaccination or older than 15 weeks were excluded. Clinical and laboratory evaluations were conducted according to a standard clinical pathway. Data were collected for relevant medical history, pregnancy outcomes, biologic agent exposure history, physical examination, laboratory results of the child, SIC recommendations for rotavirus vaccination, rotavirus vaccine series completion, and adverse events after immunisation. After parental consent, deidentified data were transferred to a central database for analysis. Children recommended for rotavirus vaccination were followed up for 8 months after series initiation to ascertain severe and serious adverse events, including severe diarrhoea, vomiting, and intussusception. FINDINGS: Between May 1, 2017, and Dec 31, 2021, 202 infants were assessed and 191 eligible infants were enrolled (97 [51%] were female and 94 [49%] were male). When including those exposed to multiple agents, the most common biologic agents to which infants were exposed were infliximab (67 [35%] of 191), adalimumab (49 [26%]), ustekinumab (18 [9%]), and vedolizumab (17 [9%]). Biologic agent exposure continued into the third trimester for 178 (93%) infants. No clinically significant abnormalities in lymphocyte subsets, quantitative immunoglobulins, or mitogen responses were detected. After SIC assessment, rotavirus vaccination was recommended for 187 (98%) of 191 infants, all of whom were followed up. By end of follow-up on Aug 19, 2022, 168 (90%) infants had initiated rotavirus vaccination; 150 (80%) completed the series. No serious adverse events after immunisation were reported, but three (2%) infants required medical attention, one for vomiting and change in stools who was subsequently diagnosed with gastroesophageal reflux disease, one for rash on labia unrelated to vaccination, and one for vomiting and diarrhoea associated with a milk allergy. INTERPRETATION: Findings from this study suggest that lymphocyte subsets and the safety of live rotavirus vaccination are generally not affected by in-utero exposure to biologic agents. Rotavirus vaccination can be offered to infants exposed to anti-TNF agents in utero. FUNDING: Public Health Agency of Canada and Canadian Institutes of Health Research through the Canadian Immunization Research Network.

Long-Term Immune Reconstitution in ADA-Deficient Patients Treated With Elapegademase: A Real-World Experience.

BACKGROUND: ADAGEN, a bovine-based enzyme replacement therapy (ERT), has been used to treat adenosine deaminase severe combined immunodeficiency (ADA-SCID). In 2018, ADAGEN was replaced by REVCOVI (elapegademase), a modified bovine recombinant protein. OBJECTIVE: To determine the real-life long-term benefits of REVCOVI in ADA-SCID. METHODS: Data on ERT, infectious and noninfectious complications, and metabolic and immune evaluations were collected from 17 patients with ADA-SCID treated for 6 months or more with REVCOVI. RESULTS: Eleven patients had previously received ADAGEN for 16 to 324 months, whereas 6 patients were ERT-naive. REVCOVI was administered twice weekly at 0.4 mg/kg/wk in ERT-naive patients, whereas patients transitioning to REVCOVI from ADAGEN typically continued at the same frequency and equivalent dosing as ADAGEN, resulting in a significantly lower (P = .007) total REVCOVI dose in the transitioning group. REVCOVI treatment in the ERT-naive group led to the resolution of many clinical and laboratory complications of ADA deficiency, whereas there were no new adverse effects among the transitioning patients. REVCOVI treatment increased plasma ADA activity and decreased dAXP (which included deoxyadenosine mono-, di-, and tri phosphate) among most patients, effects that persisted throughout the 7- to 37-month treatment periods, except in 2 patients with incomplete adherence. Among some patients, after 0.5 to 6 months, injection frequency was reduced to once a week, while maintaining adequate metabolic profiles. All ERT-naive infants treated with REVCOVI demonstrated an increase in the number of CD4+ T and CD19+ B cells, although these counts remained stable but lower than normal in most transitioning patients. CONCLUSIONS: REVCOVI is effective for the management of ADA-SCID.

Factors associated with intention for revaccination among patients with adverse events following immunization.

OBJECTIVES: Individuals and healthcare providers may be uncertain about the safety of revaccination after an adverse event following immunization (AEFI). We identified factors associated with physician recommendation for revaccination and participant intention to be revaccinated among patients with adverse events following immunization (AEFIs) assessed in the Canadian Special Immunization Clinic (SIC) Network from 2013 to 2019. METHODS: This prospective observational study included patients assessed in the Canadian Special Immunization Clinic Network from 2013 to 2019 for an AEFI who required additional doses of the vaccine temporally associated with their AEFI. Participants underwent standardized assessment and data collection. Physician recommendations regarding revaccination and participant intent for revaccination were recorded. AEFI impact on daily activities and need for medical attention was captured as low, moderate, high impact and serious (e.g., requiring hospitalization). Multivariable logistic regression analysis identified factors associated with physician recommendation and participant intention for revaccination, controlling for province of assessment. RESULTS: Physician recommendation was significantly associated with the type of AEFI and AEFI impact. Compared to large local reaction, physician recommendation for revaccination was reduced for immediate hypersensitivity (aOR: 0.24 [95% CI: 0.08-0.76]) and new onset autoimmune disease (aOR: 0.16; 95% CI: 0.04-0.69). Compared to low impact AEFIs, physician recommendation was reduced for moderate (aOR: 0.22 [95% CI: 0.07-0.65]), high impact (aOR: 0.08 [95% CI: 0.02-0.30]), and serious AEFIs (aOR: 0.11 [95% CI: 0.03-0.37]). Participant intention for revaccination was significantly associated with AEFI impact, with reduced odds for high versus low impact AEFIs (aOR: 0.12 [95% CI: 0.04-0.42]). CONCLUSION: Physicians appear to use AEFI type and impact to guide recommendations while patients use primarily AEFI impact to form intentions for revaccination. The findings may help inform counselling for patients with AEFIs.

Protocol for a living evidence synthesis on variants of concern and COVID-19 vaccine effectiveness.

BACKGROUND: It is evident that COVID-19 will remain a public health concern in the coming years, largely driven by variants of concern (VOC). It is critical to continuously monitor vaccine effectiveness as new variants emerge and new vaccines and/or boosters are developed. Systematic surveillance of the scientific evidence base is necessary to inform public health action and identify key uncertainties. Evidence syntheses may also be used to populate models to fill in research gaps and help to prepare for future public health crises. This protocol outlines the rationale and methods for a living evidence synthesis of the effectiveness of COVID-19 vaccines in reducing the morbidity and mortality associated with, and transmission of, VOC of SARS-CoV-2. METHODS: Living evidence syntheses of vaccine effectiveness will be carried out over one year for (1) a range of potential outcomes in the index individual associated with VOC (pathogenesis); and (2) transmission of VOC. The literature search will be conducted up to May 2023. Observational and database-linkage primary studies will be included, as well as RCTs. Information sources include electronic databases (MEDLINE; Embase; Cochrane, L*OVE; the CNKI and Wangfang platforms), pre-print servers (medRxiv, BiorXiv), and online repositories of grey literature. Title and abstract and full-text screening will be performed by two reviewers using a liberal accelerated method. Data extraction and risk of bias assessment will be completed by one reviewer with verification of the assessment by a second reviewer. Results from included studies will be pooled via random effects meta-analysis when appropriate, or otherwise summarized narratively. DISCUSSION: Evidence generated from our living evidence synthesis will be used to inform policy making, modelling, and prioritization of future research on the effectiveness of COVID-19 vaccines against VOC.

Antibody Seronegativity in COVID-19 RT-PCR-Positive Children.

This substudy of a prospective case-ascertained household transmission study investigated severe acute respiratory syndrome coronavirus 2 reverse transcription polymerase chain reaction-positive individuals without antibody development and factors associated with nonseroconversion. Approximately 1 of 8 individuals with coronavirus disease 2019 did not seroconvert. Children, particularly the youngest, were approximately half as likely to seroconvert compared with adults. Apart from the absence of fever/chills, individual symptoms did not strongly predict nonseroconversion.