Is it possible to conduct clinical trials during a pandemic? The example of a trial of hydroxychloroquine.

OBJECTIVES: to examine the factors that, in the context of the current pandemic, have influenced the conduct of a randomized clinical trial on hydroxychloroquine in Italy. DESIGN: the trend of enrolment in the PROTECT study, "A randomized study with Hydroxychloroquine versus observational support for prevention or early phase treatment of Coronavirus disease (COVID-19)" (Eudract number: 2020-001501-24, NCT04363827), conducted in the period from May to September 2020, was analysed to evaluate the possible association of the enrolment rate with the amount of information published in the national and local press on hydroxychloroquine. SETTING AND PARTICIPANTS: the PROTECT clinical study is an Italian interventional superiority study, open label, with cluster randomization, aimed at evaluating whether treatment with hydroxychloroquine can reduce the percentage of symptomatic subjects compared to observation only in a population of subjects exposed to SARS-CoV-2 virus consisting of cohabitants/contacts of COVID-19 patients and asymptomatic or paucisymptomatic subjects diagnosed with COVID-19. MAIN OUTCOME MEASURES: the number of asymptomatic or paucisymptomatic COVID-19 patients and the number of contacts/cohabitants of COVID-19 patients enrolled in the Protect study from May to September 2020. RESULTS: from May to September 2020, the number of patients diagnosed with COVID-19 enrolled in the PROTECT clinical trial showed a decrease consistent with the number of news on hydroxychloroquine appearing in the national and local press, starting from the time when the first criticisms of the efficacy of hydroxychloroquine were made known; the number of contacts/cohabitants of COVID-19 patients showed a more marked and more timely decrease. CONCLUSIONS: in the context determined by the current COVID-19 pandemic, conducting a controlled clinical trial is strongly influenced by public opinion on scientific issues. Adherence to a clinical study can become highly problematic and invalidate the possibility of answering a scientific question and the validity of a project. In the current pandemic situation, randomized controlled trials may not always be the optimal tool to reach the expected scientific evidence, due to a number of problems. It is preferable to use a sequential or adaptive design. Furthermore, study protocols should implement innovative approaches that also include the involvement of participants in the decision-making process. In any case, the influence of public information on scientific issues is an extremely important factor to consider in the design of clinical trials in exceptional situations such as a pandemic.

Active surveillance of adverse events after immunization (AEFI) from the Local Health Unitof Ferrara, Italy.

Introduction: Vaccine vigilance implies the collection, evaluation, analysis and communication of adverse events following immunization (AEFI) and is a useful tool for vaccine monitoring allowing, even after approval and marketing, to check its safety/tolerability. The multiregional project "Active surveillance of adverse vaccine reactions", joined by the AUSL of Ferrara, is aimed at making parents of children, who have undergone at least one vaccination provided by the regional vaccination calendar in the first 24 months of life, aware of the reporting of any AEFI via mobile phone-SMS. Methods: An analysis of the project data, collected in the period March 2018 - May 2019, was carried out, to evaluate the effectiveness of the reporting tool and the type and frequency of AEFI. Anonymized data were analyzed by number, gender, distribution by age, type of vaccine, adverse event, severity and outcome. Results: A total of 1,494 consents and 983 SMS messages were obtained from parents. The vaccine doses carried out were 1,984 (28.3% hexavalent, 28% PCV13, 17% anti-rotavirus, 14.3% Men-B). Almost all (99.5%) AEFI were classified as "not serious". Based on the Organ System Class (SOC), most reports are related to "General Disorders and Administration Site Conditions" (52.3%), followed by "Psychiatric Disorders" (26.5%) and "Metabolic and nutrition disorders" (12.5%). Conclusions: The reported AEFI are in line with the ones reported in the literature. Reporting via SMS is a valid vaccine surveillance tool contributing to the qualitative and quantitative improvement of the information transmitted.

Cholera, the Current Status of Cholera Vaccines and Recommendations for Travellers.

Cholera is endemic in approximately 50 countries, primarily in Africa and South and Southeast Asia, and in these areas, it remains a disease associated with poverty. In developed nations, cholera is rare, and cases are typically imported from endemic areas by returning travellers. Cholera is readily preventable with the tools available to modern medicine. In developing nations, cholera transmission can be prevented through improved water, sanitation, and hygiene services and the use of oral cholera vaccines (OCVs). For travellers, risk can be mitigated by practicing regular hand hygiene and consuming food and water from safe sources. OCVs should be considered for high-risk travellers likely to be exposed to cholera patients or contaminated water and food. There are currently three World Health Organization pre-qualified OCVs, which are based on killed whole-cell strains of Vibrio cholerae. These established vaccines offer significant protection in adults and children for up to 2 years. A novel live attenuated vaccine that provides rapid-onset protection in adults and children is licensed in the USA and Europe only. Live attenuated OCVs may mimic the natural infection of V. cholerae more closely, generating rapid immune responses without the need for repeat dosing. These potential benefits have prompted the ongoing development of several additional live attenuated vaccines. The objective of this article is to provide a general review of the current landscape of OCVs, including a discussion of their appropriate use in international travellers.

Varicella zoster virus vaccines: an update.

Varicella zoster virus (VZV) is the etiological agent of varicella, a highly infectious, self-limiting disease with serious complications. The decline in cell-mediated immunity (CMI) that occurs with aging or immunodepression causes a reactivation of the latent VZV as herpes zoster (HZ). Prevention of VZV through varicella vaccination strategies allows to avoid the primary infection in newborns and susceptible subjects. Available monovalent and combined VZV vaccines are effective, safe and generally well tolerated. Universal varicella vaccination has significantly impacted on incidence, complications and deaths related to this disease. Prevention of HZ through vaccination is a priority to avoid the significant burden of its incidence and complications. Currently two HZ vaccines are available. The recombinant zoster vaccine (RZV), approved by the FDA in 2017 and Zoster Vaccine Live (ZVL) licensed in the United States by the FDA in 2006. The advisory committee on immunization practices (ACIP) preferentially recommends RZV. ZVL remains an option for prevention of HZ in immunocompetent adults aged ≥60 years, although the CMI tends to wane a few years after vaccination.