Breakthrough SARS-CoV-2 Infections in the PROVENT Prevention Trial Were Not Associated with AZD7442 (Tixagevimab/Cilgavimab) Resistant Variants.

BACKGROUND: We report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of SARS-CoV-2 variants identified from breakthrough infections in the PROVENT pre-exposure prophylaxis trial (NCT04625725). METHODS: Variants identified from PROVENT participants with reverse-transcription polymerase chain reaction-positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility of variant-specific pseudotyped virus-like particles. RESULTS: At completion of 6 months' follow-up, no AZD7442-resistant variants were observed in breakthrough COVID-19 cases. SARS-CoV-2 neutralizing antibody titers were similar in breakthrough and non-breakthrough cases. CONCLUSION: Symptomatic COVID-19 breakthrough cases in PROVENT were not due to resistance-associated substitutions in AZD7442 binding sites or lack of AZD7442 exposure.

AZD7442 (Tixagevimab/Cilgavimab) for Post-exposure Prophylaxis of Symptomatic COVID-19.

BACKGROUND: We report primary results of a phase 3 trial of AZD7442 (tixagevimab/cilgavimab) for post-exposure prophylaxis to prevent symptomatic coronavirus disease 2019 (COVID-19). METHODS: Adults without prior SARS-CoV-2 infection or COVID-19 vaccination were enrolled within 8 days of exposure to a SARS-CoV-2-infected individual and randomized 2:1 to a single 300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and cilgavimab consecutively) or placebo. Primary endpoints were safety and first post-dose SARS-CoV-2 reverse-transcription-polymerase-chain-reaction (RT-PCR)-positive symptomatic COVID-19 event before day 183. RESULTS: 1121 participants were randomized and dosed (mean age 46 years; 49% females; AZD7442, n=749; placebo, n=372). Median (range) follow-up was 49 (5-115) and 48 (20-113) days for AZD7442 and placebo, respectively. Adverse events occurred in 162/749 (21.6%) and 111/372 (29.8%) participants with AZD7442 and placebo, respectively, mostly mild/moderate. RT-PCR-positive symptomatic COVID-19 occurred in 23/749 (3.1%) and 17/372 (4.6%) AZD7442- and placebo-treated participants, respectively (relative risk reduction 33.3%; 95% confidence interval [CI] -25.9 to 64.7; P=.21). In predefined subgroup analyses of 1073 (96%) participants who were SARS-CoV-2 RT-PCR-negative (n=974 [87%]) or missing an RT-PCR result (n=99 [9%]) at baseline, AZD7442 reduced RT-PCR-positive symptomatic COVID-19 by 73.2% (95% CI 27.1 to 90.1) versus placebo. CONCLUSIONS: This study did not meet the primary efficacy endpoint of post-exposure prevention of symptomatic COVID-19 with AZD7442 versus placebo. However, predefined analysis of participants who were SARS-CoV-2 RT-PCR-negative or missing an RT-PCR result at baseline support a role for AZD7442 in preventing symptomatic COVID-19.

Risk of Severe Coronavirus Disease 2019 Disease in Individuals With Down Syndrome: A Matched Cohort Study From a Large, Integrated Health Care System.

BACKGROUND: Down syndrome (DS) is associated with an increased risk of infections attributed to immune defects. Whether individuals with DS are at an increased risk of severe coronavirus disease 2019 (COVID-19) remains unclear. METHODS: In a matched cohort study, we evaluated the risk of COVID-19 infection and severe COVID-19 disease in individuals with DS and their matched counterparts in a pre-COVID-19 vaccination period at Kaiser Permanente Southern California. Multivariable Cox proportion hazard regression was used to investigate associations between DS and risk of COVID-19 infection and severe COVID-19 disease. RESULTS: Our cohort included 2541 individuals with DS and 10 164 without DS matched on age, sex, and race/ethnicity (51.6% female, 53.3% Hispanic, median age 25 years [interquartile range, 14-38]). Although the rate of COVID-19 infection in individuals with DS was 32% lower than their matched counterparts (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], .56-.83), the rate of severe COVID-19 disease was 6-fold higher (aHR, 6.14; 95% CI, 1.87-20.16). CONCLUSIONS: Although the risk of COVID-19 infection is lower, the risk of severe disease is higher in individuals with DS compared with their matched counterparts. Better infection monitoring, early treatment, and promotion of vaccine for COVID-19 are warranted for DS populations.

Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19.

BACKGROUND: The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days. METHODS: In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183. RESULTS: A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19-related deaths occurred, all in the placebo group. CONCLUSIONS: A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.).

Comparing the Clinical and Economic Outcomes Associated with Adjuvanted versus High-Dose Trivalent Influenza Vaccine among Adults Aged ≥ 65 Years in the US during the 2019-20 Influenza Season-A Retrospective Cohort Analysis.

The burden of influenza is disproportionally higher among older adults. We evaluated the relative vaccine effectiveness (rVE) of adjuvanted trivalent (aIIV3) compared to high-dose trivalent influenza vaccine (HD-IIV3e) against influenza and cardio-respiratory disease (CRD)-related hospitalizations/ER visits among adults ≥65 years during the 2019-2020 influenza season. Economic outcomes were also compared. A retrospective cohort analysis was conducted using prescription, professional fee claims, and hospital data. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding. IPTW-adjusted Poisson regression was used to evaluate the adjusted rVE of aIIV3 versus HD-IIV3e. All-cause and influenza-related healthcare resource utilization (HCRU) and costs were examined post-IPTW. Recycled predictions from generalized linear models were used to estimate adjusted costs. Adjusted analysis showed that aIIV3 (n = 798,987) was similarly effective compared to HD-IIV3e (n = 1,655,979) in preventing influenza-related hospitalizations/ER visits (rVE 3.1%; 95% CI: -2.8%; 8.6%), hospitalizations due to any cause (-0.7%; 95% CI: -1.6%; 0.3%), and any CRD-related hospitalization/ER visit (0.9%; 95% CI: 0.01%; 1.7%). Adjusted HCRU and annualized costs were also statistically insignificant between the two cohorts. The adjusted clinical and economic outcomes evaluated in this study were comparable between aIIV3 and HD-IIV3e during the 2019-2020 influenza season.

Vaccines for older adults.

The proportion of the global population aged 65 and older is rapidly increasing. Infections in this age group, most recently with SARS-CoV-2, cause substantial morbidity and mortality. Major improvements have been made in vaccines for older people, either through the addition of novel adjuvants-as in the new recombinant zoster vaccine and an adjuvanted influenza vaccine-or by increasing antigen concentration, as in influenza vaccines. In this article we review improvements in immunization for the three most important vaccine preventable diseases of aging. The recombinant zoster vaccine has an efficacy of 90% that is minimally affected by the age of the person being vaccinated and persists for more than four years. Increasing antigen dose or inclusion of adjuvant has improved the immunogenicity of influenza vaccines in older adults, although the relative effectiveness of the enhanced influenza vaccines and the durability of the immune response are the focus of ongoing clinical trials. Conjugate and polysaccharide pneumococcal vaccines have similar efficacy against invasive pneumococcal disease and pneumococcal pneumonia caused by vaccine serotypes in older adults. Their relative value varies by setting, depending on the prevalence of vaccine serotypes, largely related to conjugate vaccine coverage in children. Improved efficacy will increase public confidence and uptake of these vaccines. Co-administration of these vaccines is feasible and important for maximal uptake in older people. Development of new vaccine platforms has accelerated following the arrival of SARS-CoV-2, and will likely result in new vaccines against other pathogens in the future.