February 9, 2023

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Clinical Reports

Highly pathogenic avian influenza A(H5N1) virus infection in farmed minks, Spain, October 2022
In October 2022, an outbreak in Europe of highly pathogenic avian influenza (HPAI) A(H5N1) in intensively farmed minks occurred in northwest Spain. A single mink farm hosting more than 50,000 minks was involved. The identified viruses belong to clade 2.3.4.4b, which is responsible of the ongoing epizootic in Europe. An uncommon mutation (T271A) in the PB2 gene with potential public health implications was found. Researcher's investigations indicate onward mink transmission of the virus may have occurred in the affected farm.

Antiviral Therapeutics and Vaccines

The Negative Effect of Preexisting Immunity on Influenza Vaccine Responses Transcends the Impact of Vaccine Formulation Type and Vaccination History
The most effective measure to induce protection from influenza is vaccination. Thus, yearly vaccination is recommended, which, together with infections, establishes diverse repertoires of B cells, antibodies, and T cells. Researchers examined the impact of this accumulated immunity on human responses in adults to split, subunit, and recombinant protein-based influenza vaccines. Enzyme-linked immunosorbent assay (ELISA) assays, to quantify serum antibodies, and peptide-stimulated CD4 T-cell cytokine ELISpots revealed that preexisting levels of hemagglutinin (HA)-specific antibodies were negatively associated with gains in antibody postvaccination, while preexisting levels of CD4 T cells were negatively correlated with vaccine-induced expansion of CD4 T cells. These patterns were seen independently of the vaccine formulation administered and the subjects' influenza vaccine history. Thus, although memory CD4 T cells and serum antibodies consist of components that can enhance vaccine responses, on balance, the accumulated immunity specific for influenza A H1 and H3 proteins is associated with diminished future responses.
Prior vaccination enhances immune responses during SARS-CoV-2 breakthrough infection with early activation of memory T cells followed by production of potent neutralizing antibodies
SARS-CoV-2 infection of vaccinated individuals is increasingly common but rarely results in severe disease, likely due to the enhanced potency and accelerated kinetics of memory immune responses. However, there have been few opportunities to rigorously study early recall responses during human viral infection. To better understand human immune memory and identify potential mediators of lasting vaccine efficacy, researchers used high-dimensional flow cytometry and SARS-CoV-2 antigen probes to examine immune responses in longitudinal samples from vaccinated individuals infected during the Omicron wave. These studies revealed heightened Spike-specific responses during infection of vaccinated compared to unvaccinated individuals. Spike-specific CD4 T cells and plasmablasts expanded and CD8 T cells were robustly activated during the first week. In contrast, memory B cell activation, neutralizing antibody production, and primary responses to non-Spike antigens occurred during the second week. Collectively, these data demonstrate the functionality of vaccine-primed immune memory and highlight memory T cells as rapid responders during SARS-CoV-2 infection.
Bacillus Calmette-Guérin vaccine for prevention of COVID-19 and other respiratory tract infections in older adults with comorbidities: a randomized controlled trial
A total of 6,112 participants with a median age of 69 years (inter-quartile range 65-74) and median of 2 (inter-quartile range 1-3) comorbidities were randomized to BCG (n=3,058) or placebo (n=3,054) vaccination. COVID-19 infections were reported by 129 BCG recipients compared to 115 placebo recipients (hazard ratio (HR) 1.12; 95% confidence interval (CI) 0.87-1.44). COVID-19-related hospitalization occurred in 18 BCG and 21 placebo recipients (HR 0.86; 95% CI 0.46-1.61). During the study period 13 BCG recipients compared to 18 placebo recipients died (HR 0.71; 95% CI 0.35 - 1.43) of which 11 deaths (35%) were COVID-19 related six in the placebo group and five in the BCG group. Clinically relevant RTI was reported by 66 BCG and 72 placebo recipients (HR 0.92; 95% CI 0.66-1.28). BCG vaccination does not protect older adults with comorbidities against COVID-19, COVID-19 hospitalization or clinically relevant RTI.
Relationship between immune response to SARS-CoV2 vaccines and development of breakthrough infection in solid organ transplant recipients: the CONTRAST cohort
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in solid organ transplant (SOT) recipients is associated with poorer antibody response (AbR) compared with non-SOT recipients. However, its impact on the risk of breakthrough infection (BI) has yet to be assessed. Single-center prospective longitudinal cohort study enrolling adult SOT recipients who received SARS-CoV-2 vaccination during a 1-year period (February 2021 – January 2022), end of follow-up April 2022. Patients were tested for AbR at multiple time points. The primary end-point was BI (laboratory-confirmed SARS-CoV-2 infection ≥14 days after the second dose). Immunization (positive AbR) was considered an intermediate state between vaccination and BI. Probabilities of being in vaccination, immunization, and BI states were obtained for each type of graft and vaccination sequence using multistate survival analysis. Then, multivariable logistic regression was performed to analyze the risk of BI related to AbR levels. 614 SOT (275 kidney, 163 liver, 137 heart, 39 lung) recipients were included. Most patients (84.7%) received 3 vaccine doses. The first 2 consisted of BNT162b2 and mRNA-1273 in 73.5% and 26.5% of cases, respectively. For the third dose, mRNA-1273 was administered in 59.8% of patients. Overall, 75.4% of patients reached immunization and 18.4% developed BI. Heart transplant recipients showed the lowest probability of immunization (0.418) and the highest of BI (0.323); all mRNA-1273 vaccine sequences showed the highest probability of immunization (0.732) and the lowest of BI (0.098). Risk of BI was higher for non–high-level AbR, younger age, and shorter time from transplant. SOT patients with non–high-level AbR and shorter time from transplantation and heart recipients are at highest risk of BI.
Early Treatment with Pegylated Interferon Lambda for Covid-19
A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 and Covid-19–related hospitalization or death. The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo.
Long-term high-dose immunoglobulin successfully treats Long COVID patients with pulmonary, neurologic, and cardiologic symptoms
Researchers report nine patients suffering with Long COVID for 101 to 547 days. All exhibited significant perturbations of their immune systems, but only one was known to be immunodeficient prior to the studies directed at evaluating them for possible treatment. Neurological and cardiac symptoms were most common. Based on this data and other evidence suggesting autoimmune reactivity, we planned to treat them for 3 months with long-term high-dose immunoglobulin therapy. If there was evidence of benefit at 3 months, the regimen was continued. The patients’ ages ranged from 34 to 79 years—with five male and four female patients, respectively. All nine patients exhibited significant immune perturbations prior to treatment. One patient declined this treatment, and insurance support was not approved for two others. The other six have been treated, and all have had a significant to remarkable clinical benefit. Long-term high-dose immunoglobulin therapy is an effective therapeutic option for treating patients with Long COVID.

Epidemiology

Consistency of covid-19 trial preprints with published reports and impact for decision making: retrospective review
Comparison of characteristics of covid-19 trials with and without preprints, estimates of time to publication of covid-19 preprints, and description of differences in reporting of key methods and results between preprints and their later publications. For the effects of eight treatments on mortality and mechanical ventilation, the study comprised meta-analyses including preprints and excluding preprints at one, three, and six months after the first trial addressing the treatment became available either as a preprint or publication (120 meta-analyses in total, 60 of which included preprints and 60 of which excluded preprints) and assessed the certainty of evidence using the GRADE framework. Of 356 trials included in the study, 101 were only available as preprints, 181 as journal publications, and 74 as preprints first and subsequently published in journals. The median time to publication of preprints was about six months. Key methods and results showed few important differences between trial preprints and their subsequent published reports. Apart from two (3.3%) of 60 comparisons, point estimates were consistent between meta-analyses including preprints versus those excluding preprints as to whether they indicated benefit, no appreciable effect, or harm. For nine (15%) of 60 comparisons, the rating of the certainty of evidence was different when preprints were included versus being excluded—the certainty of evidence including preprints was higher in four comparisons and lower in five comparisons. No compelling evidence indicates that preprints provide results that are inconsistent with published papers. Preprints remain the only source of findings of many trials for several months—an unsuitable length of time in a health emergency that is not conducive to treating patients with timely evidence. The inclusion of preprints could affect the results of meta-analyses and the certainty of evidence. Evidence users should be encouraged to consider data from preprints.
Peru confirms H5N1 avian flu in marine mammals, part of southward spread.
Veterinary authorities in Peru yesterday confirmed H5N1 avian influenza in sea lions and a dolphin, adding more reports of detections in mammals as the virus continues its push into Central and South America. Peru's National Agrarian Health Service (SENASA) said surveillance for marine species on the country's coasts are part of its response to outbreaks in poultry. Tests on three sea lions found dead in November and one dolphin were positive for H5N1, SENASA said in a statement, which was translated and posted by Avian Flu Diary, an infectious disease news blog. In a follow-up, SENASA said at least 585 sea lions and 55,000 wild birds have been found dead in seven of the country's coastal nature preserves, likely due to avian flu. Also, media reports citing Peru's health ministry said tests on a zoo lion in central Peru identified H5N1 as the cause of death. The reports add to a growing number of detections in mammals, including recent reports from the United Kingdom and H5N1 in farmed minks in Spain. The United States has so far reported 110 detections in mammal species. The H5N1 clade circulating in birds, poultry, and an increasing number of mammals has a mutation that makes the virus more recognizable by mammalian airway cells. Seven human H5N1 infections have been reported, all involving people who had close contact with poultry. Some illnesses were mild, but some were severe or fatal. So far, no human-to-human transmission has been reported.
Incidence of Chronic Spontaneous Urticaria Following Receipt of the COVID-19 Vaccine Booster in Switzerland
Among 97 patients, 80 (56 [70%] female; median [IQR] age, 41 [35-49] years) agreed to participate and were assigned to the CSU-Vaud cohort. The CSU-Swiss cohort included 782 patients (446 [58%] female; median [IQR] age, 39 [33-48] years). In 72 patients (90%) in the CSU-Vaud cohort and 636 (81%) in the CSU-Swiss cohort, CSU started after the booster. The median (IQR) time between vaccination and CSU onset was 10 (8-12) days in the CSU-Vaud cohort and 11 (9-13) days in the CSU-Swiss cohort. Seventy-four cases (92%) in the CSU-Vaud and 77 (94%) in the CSU-Swiss cohort were associated with the Moderna vaccine. In the CSU-Vaud cohort, 76 participants (95%) reported taking antihistamines (taken daily in 60). Of the 80 CSU-Vaud participants, 11 (14%) reported previous urticaria, 23 (29%) reported hay fever, and 9 (11%) reported drug allergies. At data collection, 25 patients (31%) reported a diagnosis of COVID-19 infection after vaccination, with a median (IQR) delay of 51 (18-89) days. The overall crude incidence rate of CSU after a COVID-19 booster per 100 000 persons immunized with a booster was similar in the CSU-Vaud (n = 24) and CSU-Swiss (n = 19) cohorts. Compared with the Pfizer-BioNTech vaccine, the relative risk of developing CSU after the Moderna vaccine was 20.8 (95% CI, 6.5-66.0) in the CSU-Vaud cohort and 16.1 (10.8-24.0) in the CSU-Swiss cohort. The results of this cohort study suggest an association between the booster dose of mainly the Moderna vaccine and new-onset CSU. As a potential contributing mechanism warranting further investigations, researchers previously showed that the Moderna vaccine had a greater association with positive skin and basophil activation tests results compared with the Pfizer-BioNTech vaccine. Alternatively, with the Moderna vaccines containing a higher dose of mRNA and being more immunogenic than the Pfizer-BioNTech vaccine, one could speculate that the booster nonspecifically triggered CSU in predisposed individuals. These data should not discourage patients from being vaccinated. However, guidelines defining the eligibility and dosing for upcoming mRNA-based boosters are needed for patients with CSU after an mRNA-based COVID-19 vaccine.
COVID-19 Mortality and Progress Toward Vaccinating Older Adults — World Health Organization, Worldwide, 2020–2022
COVID-19 vaccines are safe and reduce COVID-19 mortality. The World Health Organization (WHO) recommends that countries prioritize populations at increased risk, e.g., older adults, for COVID-19 vaccination with a goal of 100% coverage with a completed primary series for populations at-risk. COVID-19–associated mortality among persons aged ≥60 years exceeded 80% of total COVID-19 mortality in 2020 and 2021 across all income groups; however, the median reported completed primary series coverage among older adults in 2022 was 76%, substantially below the WHO goal, especially in middle- and low-income countries.Efforts are needed to increase COVID-19 primary series and periodic booster dose coverage among older adults as recommended by WHO and national health authorities.