Aggregating human judgment probabilistic predictions of the safety,efficacy, and timing of a COVID-19 vaccine

Safe, efficacious vaccines were developed to reduce the transmission of SARS-CoV-2 during the COVID-19 pandemic. But in the middle of 2020, vaccine effectiveness, safety, and the timeline for when a vaccine would be approved and distributed to the public was uncertain. To support public health decision making, we solicited trained forecasters and experts in vaccinology and infectious disease to provide monthly probabilistic predictions from July to September of 2020 of the efficacy, safety, timing, and delivery of a COVID-19 vaccine. We found, that despite sparse historical data, a linear pool—a combination of human judgment probabilistic predictions—can quantify the uncertainty in clinical significance and timing of a potential vaccine. The linear pool underestimated how fast a therapy would show a survival benefit and the high efficacy of approved COVID-19 vaccines. However, the linear pool did make an accurate prediction for when a vaccine would be approved by the FDA. Compared to individual forecasters, the linear pool was consistently above the median of the most accurate forecasts. A linear pool is a fast and versatile method to build probabilistic predictions of a developing vaccine that is robust to poor individual predictions. Though experts and trained forecasters did underestimate the speed of development and the high efficacy of a SARS-CoV-2 vaccine, linear pool predictions can improve situational awareness for public health officials and for the public make clearer the risks, rewards, and timing of a vaccine.     

A phase 1/2 randomised placebo-controlled study of the COVID-19 vaccine mRNA-1273 in healthy Japanese adults: An interim report

IntroductionThe mRNA vaccine, mRNA-1273/TAK-919, encodes the prefusion-stabilised spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report interim results of the first study evaluating safety and immunogenicity of mRNA-1273 in healthy Japanese participants.MethodsThis phase 1/2, randomised, observer-blind, placebo-controlled trial, conducted in Japan (two sites), enrolled healthy adults aged ≥ 20 years with no prior exposure to investigational coronavirus vaccines/treatments, and no known history/risk of SARS-CoV-2 infection. Participants were stratified by age (< 65/≥ 65 years) and randomised to receive two doses of 100 μg mRNA-1273 or placebo administered as intramuscular injections 28 days apart. Primary outcomes were safety and immunogenicity assessed by anti-SARS-CoV-2-spike protein-binding antibody level (bAb). A secondary outcome was SARS-CoV-2 neutralising antibody (nAb) response.ResultsParticipants were enrolled between 21 January and 3 February 2021, and 200 were randomised: mRNA-1273, n = 150 (< 65 years, n = 100; ≥ 65 years, n = 50); placebo, n = 50 (< 65 years, n = 40; ≥ 65 years, n = 10). Solicited adverse events (AEs) through 7 days after each vaccination occurred in 144/150 (96%) and 19/50 (38%) participants in the mRNA-1273 and placebo arms, respectively. In the mRNA-1273 arm, injection-site pain, myalgia and fatigue were the most frequently reported solicited AEs after each vaccination, irrespective of age. Robust immune responses occurred with mRNA-1273 (n = 147) with a bAb geometric mean fold rise (95% confidence interval [CI]) from baseline of 1009 (865, 1177) and a nAb of 21.7 (19.8, 23.8) at day 57. Seroconversion rates (95% CI) for bAb and nAb were both 100% (97.5, 100) at day 57. No such response occurred with placebo (n = 49).ConclusionTwo doses of 100 μg mRNA-1273 given 28 days apart demonstrated an acceptable safety profile and induced significant anti-SARS-CoV-2 immune responses in a Japanese population aged ≥ 20 years. Funding: Takeda Pharmaceutical Company Limited and Japan Agency for Medical Research and Development (AMED). ClinicalTrials.gov: NCT04677660.     

Looking ahead: Caregivers’ COVID-19 vaccination intention for children 5 years old and younger using the health belief model

COVID-19 vaccine hesitancy is a significant public health issue. While vaccines are not yet available for children, clinical trials are underway, and children will likely be an important factor in the U.S. reaching herd immunity. However, little research has been conducted to examine parents’ intention to vaccinate their young children for COVID-19.MethodAn online survey with a national U.S. sample of 682 primary caregivers of children under age six assessed variables associated with intention to accept the COVID-19 vaccine for their children from November 13, 2020, to December 8, 2020.ResultsCaregivers whose child received a recent influenza vaccine, as well as those with previous experience COVID-19, were more likely to express COVID-19 vaccination intention for their young child. Identifying as female was associated with lower COVID-19 vaccination intention, while identifying as Hispanic or Latino was associated with higher intention. Health Belief Model variables of perceived severity of COVID-19 for their child, as well as vaccine confidence, were positive predictors of COVID-19 vaccine intention and mediated the relationship between prior behavior, demographic variables, and intention.ConclusionsThe findings highlight the importance of early, proactive COVID-19 vaccination education efforts directed at caregivers, including those with young children. Vaccines for young children will likely become a necessary part of ending the pandemic’s impact in school settings. Operationally, COVID-19 vaccination may also become a part of childhood vaccination schedules. Understanding the beliefs and intentions of caregivers of young children before vaccinations are recommended for children will enable public health officials and medical practitioners to prepare in advance.     

How frequent are acute reactions to COVID-19 vaccination and who is at risk?

IntroductionOur objective was to describe and compare self-reported side effects of COVID-19 vaccines in the USA.MethodsA web-based registry enrolled volunteers who received a COVID-19 vaccine between March 19–July 15, 2021. We collected self-reported short-term side effects, medical consultation, hospitalization, and quality of life impact following completed vaccination regimens (Pfizer, Moderna, J&J).ResultsWe recruited 6,966 volunteers who completed their full course of vaccination (median age 48 years, IQR 35.0–62.0; 83.6% female): Pfizer 3,486; Moderna 2,857; J&J 623. Few (3.1%) sought medical care for post-vaccination side effects. Hospitalization (n = 17; 0.3%) and severe allergic reactions (n = 39; 0.6%) also were rare. Those with autoimmune disease or lung disease were approximately twice as likely to seek medical care (adjusted odds ratio (aOR) 2.01, 95% CI:1.39; 2.92 and aOR 1.70, 95% CI: 1.12; .58 respectively). 92.4% of participants reported ≥ 1 side effect (median 3), with injection site reactions (78.9%), fatigue (70.3%), headache (49.0%) reported most frequently. More side effects were reported after the second dose of two-dose vaccines (medians: 1 vs. 2 for Pfizer and 1 vs. 3 for Moderna for first and second doses respectively) versus 3 for J&J's single-dose vaccine. For the employed, the median number of workdays missed was one. Diabetics and those vaccinated against influenza were substantially less likely to report 3 or more symptoms (aOR 0.68, 95% CI: 0.56;0.82] and aOR 0.82, 95% CI: 0.73;0.93, respectively).DiscussionThe total side effect burden was, not unexpectedly, greater with two-dose regimens but all three vaccines appear relatively safe. Very few subjects reported side effects serious enough to warrant medical care or reported post-vaccination hospitalization. While these findings do not address possible long-term effects, they do inform on their short-term safety and tolerability and will hopefully provide some reassurance and positively inform the benefit-risk and pharmacoeconomic assessment for all three vaccines.See Clinicaltrials.gov NCT04368065.     

Effective improvements to the live-attenuated Newcastle disease virus vaccine by polyethylenimine-based biomimetic silicification

Live and killed vaccines impart a significant role in preventing of Newcastle disease (ND) in China. Vaccine efficacy could be ameliorated by improving vaccine-induced cellular immunity and antibody persistency. Previous studies substantiated the potency of silicon dioxide (SiO₂) in the control-release of drugs and as a vaccine adjuvant, and polyethylenimine (PEI) merits as a mucosal adjuvanticity with electro-positivity. The present study employed SiO₂ and PEI to prepare biomimetic silicon mineralized nanoparticle G7M@SiO₂-PEI and microparticle (SiO₂ + PEI)@G7M vaccines of G7M, a candidate for live attenuated vaccine of genotype VII Newcastle disease virus (NDV). The zeta potential experiment confirmed the significant increase in the average zeta potential of the nanoparticle G7M@SiO₂-PEI and microparticle (SiO₂ + PEI)@G7M relative to G7M before mineralization. The results of RT-qPCR revealed more than 99% mineralization efficiency of the G7M@SiO₂-PEI and (SiO₂ + PEI)@G7M. The morphology detected by transmission electron microscopy reported that the diameters of G7M@SiO₂-PEI were similar to those of G7M, while for (SiO₂ + PEI)@G7M, it was about five times larger than that of G7M. Silicon was detected on the surface of both mineralization particles, except for G7M, as observed from the elemental distribution detected by elemental mapping and energy dispersive X-ray spectrogram. Indirect immunofluorescence assays validated that mineralization virus have replicated ability in BHK-21F cells. In vivo experiments revealed higher than 5.50 log₂ of antibody in nanoparticles G7M@SiO₂-PEI group until 10-week post-vaccination, and significant proliferation of antigen-specific CD3⁺CD4⁺ in nanoparticles G7M@SiO₂-PEI immunized group corroborated improved cellular immune responses. Vaccines provided full protection to the immunized chickens, whereas all the chickens receiving mock immunizations succumbed to the disease. Overall, our study concluded the efficacy of biomimetic mineralization of live attenuated vaccine in nanoparticles to improve humoral and cellular immune responses.     

Acute unsolicited adverse events following BNT162b2 vaccine in Saudi Arabia,a real-world data

BackgroundAcute adverse events and anaphylaxis were reported after the administration of coronavirus disease (COVID-19) mRNA vaccines. We aim to explore the nature and outcome of adverse events following BNT162B2 vaccine in a community vaccination center, Riyadh, Saudi Arabia.MethodWithin 30 min post vaccination, all acute adverse events (AAEs) that occurred before March 31st, 2021, and in people older than 16 years were reviewed (AAE group). We used the case definition of Brighton collaboration on vaccine safety to define anaphylaxis. Patients’ demographics, comorbidities, allergy history, and outcome at disposition were collected. Observation duration after vaccination was short (<15 min) or extended (<3 h). Statistical analysis was performed to study AAEs association with the study variables and outcomes.ResultsOut of 71,221 vaccine recipients, 144 (0.002%) had developed 345 AAEs, at a rate of 48.4 events per 10,000 dose administered. The majority of cases in AAE group were first dose recipients (93.8%) and previously healthy (59%), while the minority had a previous history of allergy (6.3%) or a laboratory-confirmed COVID-19 (4.2%). We found a significant association between female gender and the occurrence of any AAE (p-value = 0.002). Per every 10,000 doses administered, non-anaphylactic AAEs were dizziness (17.8), headache (9.7), nausea (7.1), or syncope (3.2). Only one in every ten AAEs was considered serious and resulted in an extended observation (4.8 per 10,000 doses), but only 1/144 required hospitalization for non-anaphylaxis reasons (0.1 per 10,000 doses). According to the Brighton collaboration definition of anaphylaxis, no single case of high certainty anaphylaxis was recorded. No death was documented in this cohort.ConclusionAcute adverse events due to BNT162b2 vaccine were rare and mostly non-serious with a tendency to occur more in women. Further prospective studies on larger vaccine recipients to evaluate the incidence of anaphylaxis in the Saudi population are warranted.     

Safety of measles and pertussis-containing vaccines in children with autism spectrum disorders

ObjectivesTo determine whether children aged 4–7 years with a diagnosis of autism spectrum disorders (ASD) were at increased risk of fever, febrile seizures, or emergency department (ED) visits following measles- or pertussis-containing vaccines compared with children without ASD.MethodsThe study included children born between 1995–2012, aged 4–7 years at vaccination, and members of six healthcare delivery systems within Vaccine Safety Datalink. We conducted self-controlled risk interval analyses comparing rates of outcomes in risk and control intervals within each group defined by ASD status, and then compared outcome rates between children with and without ASD, in risk and control intervals, by estimating difference-in-differences using logistic regressions.ResultsThe study included 14,947 children with ASD and 1,650,041 children without ASD. After measles- or pertussis-containing vaccination, there were no differences in association between children with and without ASD for fever (ratio of rate ratio for measles-containing vaccine = 1.07, 95% CI 0.58–1.96; for pertussis-containing vaccine = 1.16, 95% CI 0.63–2.15) or ED visits (ratio of rate ratio for measles-containing vaccine = 1.11, 95% CI 0.80–1.54; for pertussis-containing vaccine = 0.87, 95% CI 0.59–1.28). Febrile seizures were rare. Pertussis-containing vaccines were associated with small increased risk of febrile seizures in children without ASD.ConclusionChildren with ASD were not at increased risk for fever or ED visits compared with children without ASD following measles- or pertussis-containing vaccines. These results may provide further reassurance that these vaccines are safe for all children, including those with ASD.     

Increases in human papillomavirus vaccine coverage over 12 months among a community-recruited cohort of gay,bisexual, and other men who have sex with men in Canada

BackgroundStarting in 2015/16, most Canadian provinces introduced publicly-funded human papillomavirus (HPV) vaccination programs for gay, bisexual, and other men who have sex with men (GBM) aged ≤ 26 years. We estimated 12-month changes in HPV vaccine coverage among community-recruited GBM from 2017 to 2021 and identified baseline factors associated with vaccine initiation (≥1 dose) or series completion (3 doses) among participants who were unvaccinated or partially vaccinated at baseline.MethodsWe recruited sexually-active GBM aged ≥ 16 years in Montreal, Toronto, and Vancouver, Canada, from 02/2017 to 08/2019 and followed them over a median of 12 months (interquartile range = 12–13 months). We calculated the proportion who initiated vaccination (≥1 dose) or completed the series (3 doses) by 12-month follow-up. Analyses were stratified by city and age-eligibility for the publicly-funded programs at baseline (≤26 years or > 26 years). We used multivariable logistic regression to identify baseline factors associated with self-reported incident vaccine initiation or series completion.ResultsAmong 165 unvaccinated participants aged ≤ 26 years at baseline, incident vaccine initiation (≥1 dose) during follow-up was 24.1% in Montreal, 33.3% in Toronto, and 38.9% in Vancouver. Among 1,059 unvaccinated participants aged > 26 years, incident vaccine initiation was 3.4%, 8.9%, and 10.9%, respectively. Higher education and trying to access pre-exposure prophylaxis for HIV were associated with incident vaccination among those aged ≤ 26 years, while younger age, residing in Vancouver (vs. Montreal), being diagnosed with anogenital warts, having both government and private extended medical insurance, and being vaccinated against influenza were associated with incident vaccination among those aged > 26 years.ConclusionsWe observed substantial gains in HPV vaccine coverage among young GBM within 5 + years of targeted program implementation, but gaps remain, particularly among older men who are ineligible for publicly-funded programs. Findings suggest the need for expanded public funding or insurance coverage for HPV vaccines.     

Differences in clinical outcomes of COVID-19 among vaccinated and unvaccinated kidney transplant recipients

IntroductionThe remarkable efficacy and effectiveness of COVID-19 vaccines have been described in healthy individuals, but kidney transplant recipients have been excluded from these studies. Therefore, real-world evidence of these vaccines can guide clinicians in predicting complications in kidney transplant recipients and how many doses of vaccines are protective. In this study, we aimed to investigate the impact of the COVID-19 vaccines on kidney transplant recipients with SARS-CoV-2 infection.Material and methodThis matched case-control study included vaccinated kidney transplant recipients with COVID-19 from two centers between 1 May and 1 October 2021. All patients in the vaccinated group received a minimum of two doses of the vaccine and were diagnosed with COVID-19 at least one month after the last dose. Each vaccinated patient was matched with an unvaccinated kidney transplant recipient diagnosed with COVID. The endpoints were all-cause mortality, hospitalization, intensive care unit admission, acute kidney injury, cytokine storm, and acute respiratory distress syndrome.ResultsThe median age of vaccinated seventy-two participants was 45 years, and 41 of the participants were men in the vaccinated group. Four patients in the vaccinated group and nine patients in the control group died during follow-up (p = 0.247). Seventeen patients in the vaccinated group, thirty-four participants in the control group were hospitalized (p = 0.004); five vaccinated patients and ten unvaccinated patients were followed-up in the ICU during follow-up (p = 0.168). Thirteen of the vaccinated and twelve unvaccinated patients developed acute kidney injury (p = 0.16). The occurrence of cytokine storm (n = 4 vs. n = 11; p = 0.061) and acute respiratory distress syndrome (n = 5 vs. n = 10; p = 0.168) was higher in the patient group compared to the control group.ConclusionCOVID-19 remains a fatal disease despite advancing treatment modalities and preventive strategies. COVID-19 vaccines can't prevent death in all kidney transplant recipients, but they decrease hospitalization rate and duration in most patients.