PROTECTION AGAINST HETEROLOGOUS CHALLENGE 1 YEAR AFTER INFANT SARS-CoV-2 IMMUNIZATION

Background: Although mRNA SARS-CoV-2 vaccines have received emergencyuse- authorization for infants age 6 months and older, vaccine uptake is slow, stressing that questions of safety and durability of vaccine efficacy remain prominent. Method(s): Infant rhesus macaques (RMs) (n=8/group) at 2 months of age, comparable to human toddler age, were immunized intramuscularly at weeks 0 and 4 with 30mug stabilized prefusion SARS-CoV-2 S-2P spike (S) protein (Washington strain) encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or 15mug S protein mixed with 3M-052 in stable emulsion (Protein). At 1 year, vaccinated and age-matched unvaccinated RM (n=8) were challenged intranasally (106pfu) and intratracheally (2x106pfu) with B.1.617.2. Lung radiographs and pathology were blindly assessed, viral N gene RNA (vRNA) copies were measured by qPCR in pharyngeal swabs and lung, and neutralizing antibody and peripheral blood T cell responses were measured. Result(s): At 1 year, D614G-specific neutralizing antibody (nAb) titers were still detectable in the Protein (ID50=755;range: 359-1,949) and mRNA-LNP groups (ID50=73;range: 41-240). Both vaccines also induced cross-neutralizing antibodies to B.1.617.2. Peripheral blood CD4+ T cell responses to the ancestral spike protein at week 52 did not differ between the groups. However, median CD8+ T cell responses were higher (p=0.002, Mann Whitney) in the mRNA-LNP group (2.8%;range: 0.9%-7.1%) compared to the Protein group (0.8%;range: 0.1%-1.6%). Control RMs had significantly higher median vRNA copies/ml (1.4+/-2.7x108) in day 4 pharyngeal swabs compared to Protein (3.8+/-6.8x103) or mRNA-LNP (4.4+/-9.7x105) vaccinated RMs. Severe lung pathology was observed in 7 of 8 controls compared to 1 of 8 or 0 of 8 RMs in the mRNA-LNP or Protein group respectively. Protection against lung inflammation was associated with nAb titers (r=-0.592, p=0.003) (Figure 1). Conclusion(s): These results demonstrate that despite lower vaccine doses compared to adults, both protein and mRNA vaccines were safe, induced durable immune responses and provided comparable protective efficacy against infection with a heterologous SARS-CoV-2 variant in infants, implying that early life vaccination of human infants may lead to durable immunity. Neutralizing ID50 antibody titers are a correlate of protection in infant RMs challenged with SARS-CoV-2.

Humoral immune responses to COVID-19 vaccines are reduced in patients with severe asthma

Background: Patients with severe asthma (SA) may be at higher risk of severe COVID-19 (C-19) illness. C-19 vaccines aim to reduce number and severity of infections. Patients with SA are often treated with maintenance oral corticosteroids (mOCS) and/or biologics (mAb)- it is unknown if vaccines will generate the same protective responses in patients with SA on such therapies. Aim(s): To compare magnitude and range of post-vaccination (PV) antibody responses (IgG) in patients with SA on mAb, mOCS or high-dose inhaled corticosteroids (ICS) with healthy controls (HC) without asthma. Method(s): The Virtus finger-prick quantitative C-19 antibody test was used to detect IgG levels 16-24 weeks post second-dose of the C-19 vaccine (123 AstraZeneca, 56 Pfizer, 5 Moderna). IgG>0.2AU was considered positive with range: very high >1.25AU, high 0.751-1.25AU, medium 0.401-0.75AU and low 0.201-0.4AU. SA was defined as per ATS/ERS criteria. Result(s): PV IgG results were obtained from 127 patients with SA (84 mAb, 13 mOCS and 46 ICS) and 57 HC. After adjusting for age, significantly fewer people with SA compared to HC had a positive PV IgG result (81% vs 95% p=0.016). Lower median IgG levels were seen in patients on mOCS (0.40AU) compared to HC (1.24AU) (p=0.051). Patients on mAb had high or very high IgG levels (omalizumab n=25, 0.80AU;mepolizumab n=25, 1.07AU;benralizumab n=34, 1.11AU). Conclusion(s): Overall, a higher proportion of patients with SA had a negative PV IgG level after receiving 2 doses of a C-19 vaccine. This was mainly seen in patients on mOCS while mAb use was associated with high levels of humoral antibody response. These results reinforce the need for booster vaccines in SA, especially in those on mOCS.

Safety and Immunogenicity of a Bivalent Omicron-Containing Booster Vaccine against COVID-19

Background. Vaccination strategies that provide enhanced immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are needed. We evaluated the safety and immunogenicity of a bivalent omicron containing vaccine, mRNA-1273.214 (50 mug), administered as a second booster dose in adult participants. Methods. In this ongoing phase 2/3 trial, 50 mug of the bivalent vaccine mRNA-1273.214 (25 mug each ancestral Wuhan-Hu-1 and omicron BA.1 spike mRNAs) or 50 mug of the authorized mRNA-1273 were administered as second boosters in adults who previously received a 2 dose (100 mug) primary series and a first booster (50 mug) dose of mRNA-1273 (>= 3 months prior). Primary objectives were safety and reactogenicity and immunogenicity 28 days post-booster dose. Results. In participants with no prior SARS-CoV-2 infection who received booster doses of mRNA-1273.214 (n=334) or mRNA-1273 (n=260), neutralizing antibody (nAb) geometric mean titers (GMTs [95% confidence interval (CI)]) against omicron BA.1 were 2372.4 (2070.6-2718.2) and 1473.5 (1270.8-1708.4), respectively. The model-based GMT ratio (GMR [97.5% CI]) of mRNA-1273.214 compared to mRNA-1273 was 1.75 (1.49-2.04), meeting the pre-specified superiority criterion against omicron BA.1. The pre-specified criterion for non-inferiority against the ancestral SARS-CoV-2 strain was also met. Additionally, mRNA-1273.214 elicited higher GMTs (727.4 [632.8-836.1]) than mRNA-1273 (492.1 [431.1-561.9]) against omicron subvariants BA.4/BA.5 [GMR (95% CI) 1.69 [1.51-1.90])]. Binding antibody responses against alpha, beta, gamma, delta, and omicron were numerically higher in the mRNA-1273.214 group compared to mRNA-1273. mRNA-1273.214 GMTs were consistently higher across age (18-< 65 and >= 65 years) and pre-booster SARS-CoV-2 infection subgroups (Figure). Safety and reactogenicity were similar for both vaccine groups. Conclusion. The bivalent omicron containing mRNA-1273.214 elicited superior nAb responses against omicron 28 days post-immunization compared to mRNA-1273 regardless of age and prior SARS-CoV-2 infection;no new safety concerns were identified. (Figure Presented).

Humoral immune responses to COVID-19 vaccines are reduced in patients with severe asthma

BackgroundPatients with severe asthma (SA) may be at higher risk of severe COVID-19 (C-19) illness. C-19 vaccines aim to reduce number and severity of infections. Patients with SA are often treated with maintenance oral corticosteroids (mOCS) and/or biologics- it is unknown if vaccines will generate the same protective responses in patients with SA on such therapies.AimsTo compare magnitude and range of post-vaccination (PV) antibody responses (IgG) in patients with SA on biologics, mOCS or high-dose inhaled corticosteroids (ICS) with healthy controls (HC) without asthma.To review temporal trends in PV IgG in patients with SAMethodsThe Virtus finger-prick quantitative C-19 antibody test was used to detect IgG levels 16–24 weeks post second-dose of the C-19 vaccine (123 AstraZeneca, 56 Pfizer, 5 Moderna). PV IgG levels were also measured in a subset of patients 6 weeks PV. IgG>0.2 AU was considered positive with range: very high >1.25 AU, high 0.751–1.25 AU, medium 0.401–0.75 AU and low 0.201–0.4 AU. SA was defined as per ATS/ERS criteria.ResultsPV IgG results were obtained from 127 patients with SA (84 on biologics, 13 mOCS and 46 ICS) and 57 HC. After adjusting for age, significantly fewer people with SA compared to HC had a positive PV IgG result (81% vs 95% p=0.016). Compared to HC (1.24 AU), lower median IgG levels were seen in patients on high dose ICS (1.02 AU, p=0.033) and mOCS (0.40 AU, p=0.017).Patients on biologics had high or very high IgG levels (omalizumab n=25, 0.80 AU;mepolizumab n=25, 1.07 AU;benralizumab n=34, 1.11 AU).Paired temporal measurements in 37 SA patients showed regression coefficient -0.005 (95%CI -0.006,-0.003) and can be interpreted as IgG decreases, on average, by 0.15 AU per month.ConclusionOverall, a higher proportion of patients with SA had a negative PV IgG level after receiving 2 doses of a C-19 vaccine. This was mainly seen in patients on mOCS while biologic use was not associated with reduced humoral antibody response. These results reinforce the need for booster vaccines in SA, especially in those on mOCS.

A rapid review of innovations for attraction, recruitment and retention of social care workers, and exploration of factors influencing turnover within the UK context

Context: The UK social care sector has come under increased pressure to combat workforce shortages. With international recruitment of professionals impacted by Brexit and the COVID-19 pandemic, social care is in need of innovations to attract, recruit and retain staff. Objectives: This review aimed to identify (1) innovations to attract, recruit, and retain social workers (professionals working with children and adults to protect them from harm, often as case managers) and the wider social care workforce (workers providing direct practical support to children and adults with their daily activities) and (2) factors influencing staff turnover in the UK context. Method: Pre-defined inclusion criteria were developed using the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) framework. Searches were conducted across three databases and 32 key United Kingdom third sector and government organisations from 2001. In total, 1,835 citations were retrieved and 40 met the eligibility criteria (13 for social workers and 28 for social care workforce). Thematic analysis was used to explore the data and presented across two evidence maps. Findings: Evaluation evidence was only available for a small portion of innovations identified. Practice learning, fast-track graduate programmes, and apprenticeships may support the retention of social workers, while pre-employment training, national recruitment campaigns, care work ambassadors, and values-based recruitment could help attraction, recruitment, and retention of the wider social care workforce. Limitations: Most of the included studies were conducted pre-pandemic and mainly relied on descriptive and explorative methodologies. Implications: Future policy initiatives should include an evaluation strategy from the outset to develop a more extensive evidence base. Funding bodies should offer schemes supporting research in this area. © 2022 The Author(s).

THE ALPHA COLLABORATION FOR RANDOMISED MEGA-STUDIES TO IMPROVE MORTALITY AND DISABILITY

Background: COVID-19 trials took <1 year to identify therapies reducing death in >30,000 patients but the Australian Placental Transfusion Study took >12 years to show that delaying cord clamping reduced death or major disability (cerebral palsy, severe visual loss, deafness, or cognitive delay) in 1,531 preterm infants. What can this teach us? Further, as composite outcomes of death or major disability can be inconclusive if each is unequally affected (as in the NeOProM Collaboration1) 2 important aims are (i) global co-operation (https://www.alphacollaboration.com/) to identify core Participant-Intervention-Comparator-Outcome questions for trials assessing mortality, a key outcome, and (ii) to answer those questions in much larger, faster trials. Such trials will also yield much more precise estimates of disability in survivors than was previously typical - a major benefit. Method: To inform these aims we compared enrolment in 2 COVID-19 trials and in 10 trials by IMPACT collaborators with samples >1,500 in high- or low-or-middle-income countries (HIC/LMIC). Results: The COVID-19 trials took 3-9 months, enrolling 13 - 219 per-site-per-year. Perinatal trials took 16-86 months, enrolling 5 - 1,700 per site per year. Trials in pregnant women or LMIC (n = 53,092) enrolled 5 times more than trials in newborns or restricted to HIC (n = 9,014). (Table) Conclusions: Greater international collaboration could resolve questions of shared relevance and priority more rapidly. Megatrials addressing mortality may benefit from highly streamlined processes for enrolment and minimal data collection, e.g., RECOVERY's one-page outcome form.

Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains

[Figure: see text].

Allelic variation in class I HLA determines CD8(+) T cell repertoire shape and cross-reactive memory responses to SARS-CoV-2

[Figure: see text].

Sensitivity and specificity of fecal immunochemical test (FIT) for patients referred with symptoms suggestive of colorectal cancer

Purpose/Background: Faecal immunochemical test (FIT) is widely adopted for the screening of colorectal cancer in the United Kingdom. At the start of the coronavirus pandemic we incorporated FIT testing into our department's urgent referral pathway for patients with suspected colorectal cancer. This aimed to triage those symptomatic patients who required urgent investigation and those who were unlikely to have significant colorectal pathology and therefore could have investigations delayed until it was safer and endoscopy services had recovered capacity. This study aimed to identify the diagnostic accuracy of FIT in this setting. Methods/Interventions: Patients referred to our institution under our urgent cancer referral pathway between 28th April and 19th June 2020 were identified from a prospectively kept database. FIT results were accessed from electronic laboratory records. Results were analysed using a threshold of 10ug/ml and the current screening threshold in England of 120ug/ml. Patient outcomes were determined by electronic patient records. Significant polyps included polyps greater than 10mm or meeting British Society of Gastroenterology high risk criteria. Results/Outcome(s): 373 patients were referred to the colorectal department during the study period. 24 referrals did not meet urgent referral criteria. 202 (54%) patients had FIT performed by their general practitioner and 47 (13%) patients had FIT undertaken in the colorectal clinic. In patients who had FIT, 97 (41%) patients had a FIT result less than 10ug/ml and 193 (81%) patients had FIT less than 120ug/ml. 25 (10%) patients were not investigated further based on FIT result and 16 (6%) patients declined further investigation. 13 (3%) patients in the cohort were subsequently investigated and diagnosed with a colorectal cancer (FIT range 24-8438ug/ml). One patient was diagnosed with a gastric cancer (FIT 259ug/ml) and two other patients had incidental findings of other nongastrointestinal cancers. 9 (4%) and 19 (8%) patients had significant colonic polyps and colitis respectively. Other diagnoses included bleeding gastric ulcer (2), angiodysplasia (1) and solitary rectal ulcer syndrome (1). In this symptomatic cohort, with a threshold of 10ug/ml the sensitivity of FIT was 100% and specificity of 36% for the diagnosis of colorectal cancer. At the 120ug/ml threshold the sensitivity was 77% and the specificity 81% for the diagnosis of colorectal cancer. Conclusions/Discussion: Incorporating FIT to triage symptomatic patients with symptoms suggestive of colorectal cancer is feasible with acceptable levels of diagnostic accuracy when utilizing a threshold of 10ug/ml. FIT testing will continue to be incorporated into our urgent cancer referral pathway, although general practitioners may still refer patients with a negative FIT but high clinical suspicion. Further work will continue to audit the use of FIT in this symptomatic setting.

Sars-cov-2 vaccines induce durable neutralizing antibodies in infant rhesus macaques

Background: SARS-CoV-2 vaccines have shown promising efficacy in human adult trials, but immunogenicity and efficacy studies in the pediatric population are lagging behind. Here we evaluated the immunogenicity of two prefusion stabilized Spike protein (S-2P) vaccine platforms in infant Rhesus Macaques (RM): an adjuvanted S-P2 subunit and mRNA vaccine. Methods: Infant RMs (2.5 months-old) were immunized intramuscularly at weeks (wks) 0 & 4 with 15 μg S-P2 adjuvanted with the toll-like receptor 7/8 agonist 3M-052 in stable emulsion (n=8), or 30 μg of S-P2 mRNA in lipid nanoparticles (mRNA-LNP, Moderna) (n=8). Blood was collected at wks 0, 4, 6, 8, & 14. Plasma (Spike[S]) and salivary (receptor binding domain [RBD]) IgG responses were measured by ELISA and epitope specificity by multiparameter bead array. Antibody function was assessed by an ACE2 blocking assay and neutralization by pseudovirus (PSVA) and whole virus neutralization assays, both with D614G. Flow cytometry was applied to measure S-specific memory B cells using fluorochrome-conjugated recombinant S, and S-specific IL-2, IL-17, TNF-α, or IFN-γ producing T cells after stimulation with overlapping peptides of full-length S. Results: No adverse effects were observed with either vaccine. Plasma S-specific IgG responses were induced by both vaccines at wk 4, increased after the second dose, and persisted through wk 14 (Fig 1A). All S regions were targeted by plasma IgG (Fig 1B), and RBD-specific IgG was also detected in saliva. Serum antibodies achieved >95% ACE2 blocking by wk 6 (1:10 dilution), remaining >90% at wk 14. Geometric mean ID50 titers of neutralizing antibodies in the PSVA exceeded 10[3] from wk 6 through wk 14 (Fig 1C) and strongly correlated with whole virion neutralization (p<0.0001). In the protein vaccine group, S-specific CD27+ memory B cells peaked at 3.1% (mean) of total memory B cells;and S-specific CD4+ T cell responses were dominated by IL-17 and IFN-γ Mean S-specific CD27+ B cells peaked at 0.9% total memory B cells in mRNA vaccinees and S-specific CD4+ T cells produced IL-2, IFN-γ, IL-17, or TNF-α. Conclusion: The S-2P-3M-052-SE and mRNA-LNP vaccines were well-tolerated and highly immunogenic in infant Rhesus Macaques, with persistent IgG binding and neutralization responses that are comparable to those reported for adult RMs and humans. Our results provide proof-of-concept that a pediatric SARS-CoV-2 vaccine could induce long term protection against SARS-CoV-2.

Norwich COVID-19 testing initiative pilot: evaluating the feasibility of asymptomatic testing on a university campus.

BACKGROUND: There is a high prevalence of COVID-19 in university-age students, who are returning to campuses. There is little evidence regarding the feasibility of universal, asymptomatic testing to help control outbreaks in this population. This study aimed to pilot mass COVID-19 testing on a university research park, to assess the feasibility and acceptability of scaling up testing to all staff and students. METHODS: This was a cross-sectional feasibility study on a university research park in the East of England. All staff and students (5625) were eligible to participate. All participants were offered four PCR swabs, which they self-administered over two weeks. Outcome measures included uptake, drop-out rate, positivity rates, participant acceptability measures, laboratory processing measures, data collection and management measures. RESULTS: 798 (76%) of 1053 who registered provided at least one swab; 687 (86%) provided all four; 792 (99%) of 798 who submitted at least one swab had all negative results and 6 participants had one inconclusive result. There were no positive results. 458 (57%) of 798 participants responded to a post-testing survey, demonstrating a mean acceptability score of 4.51/5, with five being the most positive. CONCLUSIONS: Repeated self-testing for COVID-19 using PCR is feasible and acceptable to a university population.

Giving Psychology Trainees a Voice During the COVID-19 Pandemic: Trainee Mental Health, Perceived Safety, and Support

The impact of infectious disease outbreaks on mental health among health care workers is wellestablished. Minimal research has focused on health care trainees' well-being, especially during unprecedented events such as the 2019 coronavirus pandemic (COVID-19). Trainees are vulnerable to inherent power and resource differentials, which may exacerbate stress. The present study used a mixed methods approach to examine mental health symptoms, perceived safety, and ongoing and desired support among a national sample of psychology interns, psychology intern and postdoctoral trainees during the COVID-19 pandemic (N = 400). Participants reported clinically elevated anxiety and depressive symptoms. Participants working on-site who felt that their health or safety was at risk reported more anxiety symptoms. Most common workplace safety concerns included inadequate protection against risk and face-to-face patient care requirements. Trainees desired more support, better communication, more remote work and telehealth options, and flexibility in training requirements. Themes also emerged related to supervisor pressure and disregard of trainees' concerns. Results have significant implications for the training environment and quality of patient care. Increased support of psychology trainees is vital during the current and potential future public health crises. © 2020 American Psychological Association.