Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials: A Systematic Review and Meta-analysis.

Importance: Adverse events (AEs) after placebo treatment are common in randomized clinical drug trials. Systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide especially because concern about AEs is reported to be a reason for vaccination hesitancy. Objective: To compare the frequencies of AEs reported in the placebo groups of COVID-19 vaccine trials with those reported in the vaccine groups. Data Sources: For this systematic review and meta-analysis, the Medline (PubMed) and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched systematically using medical subheading terms and free-text keywords for trials of COVID-19 vaccines published up to July 14, 2021. Study Selection: Randomized clinical trials of COVID-19 vaccines that investigated adults aged 16 years or older were selected if they assessed solicited AEs within 7 days of injection, included an inert placebo arm, and provided AE reports for both the vaccine and placebo groups separately. Full texts were reviewed for eligibility by 2 independent reviewers. Data Extraction and Synthesis: Data extraction and quality assessment were performed independently by 2 reviewers, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline and using the Cochrane risk-of-bias tool. Meta-analyses were based on random-effects models. Main Outcomes and Measures: The primary outcomes were the proportions of placebo recipients reporting overall, systemic, and local (injection-site) AEs as well as logarithmic odds ratios (ORs) to evaluate group differences. Outcomes were tested for significance using z tests with 95% CIs. Results: Twelve articles with AE reports for 45 380 participants (22 578 placebo recipients and 22 802 vaccine recipients) were analyzed. After the first dose, 35.2% (95% CI, 26.7%-43.7%) of placebo recipients experienced systemic AEs, with headache (19.3%; 95% CI, 13.6%-25.1%) and fatigue (16.7%; 95% CI, 9.8%-23.6%) being most common. After the second dose, 31.8% (95% CI, 28.7%-35.0%) of placebo recipients reported systemic AEs. The ratio between placebo and vaccine arms showed that nocebo responses accounted for 76.0% of systemic AEs after the first COVID-19 vaccine dose and for 51.8% after the second dose. Significantly more vaccine recipients reported AEs, but the group difference for systemic AEs was small after the first dose (OR, -0.47; 95% CI, -0.54 to -0.40; P < .001; standardized mean difference, -0.26; 95% CI, -0.30 to -0.22) and large after the second dose (OR, -1.36; 95% CI, -1.86 to -0.86; P < .001; standardized mean difference, -0.75; 95% CI, -1.03 to -0.47). Conclusions and Relevance: In this systematic review and meta-analysis, significantly more AEs were reported in vaccine groups compared with placebo groups, but the rates of reported AEs in the placebo arms were still substantial. Public vaccination programs should consider these high rates of AEs in placebo arms.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Challenge Experiments in Nonhuman Primates: An Ethical Perspective.

The coronavirus disease 2019 (COVID-19) pandemic has stimulated massive investment in biomedical research with the aims of understanding the disease and developing effective vaccine and therapeutic interventions. What role should animal research play in this scientific endeavor? Both the urgency to evaluate candidate interventions for human use and growing societal concern about ethical treatment of (nonhuman) animals put into question the justifiability of animal research as a precursor to clinical trials. Yet forgoing animal research in the rush to undertake human testing might expose human research participants to unacceptable risks. In this article, we apply a recently developed framework of principles for animal research ethics in exploring ethical questions raised by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection challenge experiment involving rhesus macaques, which evaluated the protective efficacy of the mRNA-1273 vaccine that was recently approved for emergency use. Our aim is to illuminate the ethical issues while introducing, and illustrating the use of, the framework.

The Legality and Ethics of Mandating COVID-19 Vaccination.

In light of ongoing concerns in the US that COVID-19 vaccine uptake is stagnating and that cases remain high amongst the unvaccinated, there is growing interest in increasing uptake by mandating vaccination. COVID-19 vaccine mandates must be understood and assessed in terms of who is requiring vaccination and who is required to be vaccinated. This essay considers the legal and ethical implications of states mandating vaccination for children and adults, as well as of employers mandating vaccines for employees. We conclude that COVID-19 vaccine mandates are legally and ethically permissible.

Liberty and Protection of Society During a Pandemic: Revisiting John Stuart Mill.

John Stuart Mill's classic text, On Liberty, maps the scope and limits on individual freedom. His "harm principle"-that liberty can be legitimately restricted by government or society only to prevent harm to others-has had a great influence on contemporary public health ethics. This essay examines Mill's philosophy of liberty as it pertains to public health interventions in response to the coronavirus pandemic. Particular applications include examination of face masks, lockdowns, and mandatory vaccination.

Human Infection Challenge Experiments: Then and Now.

In the midst of the Covid-19 pandemic, ethicists, researchers, and journalists have recommended studies that deliberately infect healthy volunteers with the coronavirus as a scientific means of expediting vaccine development. In this essay, we trace the history of infection challenge experiments and reflect on the Nuremberg Code of 1947, issued in response to brutal human experiments conducted by Nazi investigators in concentration camps. We argue that the Code continues to offer valuable guidance for assessing the ethics of this controversial form of research, with respect particularly to the acceptable limits to research risks and the social value of research necessary to justify exposing human participants to these risks.

Allocating a COVID-19 Vaccine: Balancing National and International Responsibilities.

Policy Points In this paper we propose a middle-ground policy for the distribution of an effective COVID-19 vaccine, between a cosmopolitan approach that rejects entirely nation-state priority and unbridled vaccine nationalism that disregards obligations to promote an equitable global allocation of an effective vaccine over time. Features of the COVAX partnership, a collaboration among the Global Alliance for Vaccines and Immunizations (GAVI), the Coalition for Epidemic Preparedness Innovations (CEPI), and the World Health Organization (WHO) to develop and distribute COVID-19 vaccines make it an appropriate framework for a middle-ground policy.

The Ethics of Everyday Life in the Midst of a Pandemic.

Elderly individuals are at higher risk of serious illness and death if they become infected by the coronavirus. During the current pandemic, my wife and I, at ages seventy-two and seventy-one, respectively, have been paying a person laid off from a job to purchase groceries-a practice that exposes the shopper to risk of infection for our benefit. In this essay, I examine this practice with respect to the normative concepts of treating another person as a means, coercion, exploitation, and complicity.