key: cord-0945220-i6my18ae authors: Bruel, Sébastien; Gagneux-Brunon, Amandine; Charles, Rodolphe; Gocko, Xavier; Botelho-Nevers, Élisabeth title: Reprint of: Development of vaccines and vaccinal strategies against COVID-19: the information contributing to shared decision-making date: 2022-04-09 journal: La Presse Médicale Open DOI: 10.1016/j.lpmope.2022.100024 sha: bbaa912ecfb0cc10e40600d4f87744f879735c25 doc_id: 945220 cord_uid: i6my18ae The public has many questions about COVID-19 vaccines. The informing of general practitioners and other vaccinators provides healthcare users with clear and reliable information conducive to shared decision-making. While they constitute a bulwark against widespread vaccine hesitancy, informative supports can be tainted by doubt if they are not backed up by solid arguments convincingly addressing the manifold questions and concerns of healthcare users. In December 2019, an epidemic caused by an emerging virus known as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2, due to its similarities with SARS-CoV, which appeared in 2003) broke out in the city of Wuhan, China. On 11 March 2020 the World Health Organization (WHO) characterized the phenomenon as a pandemic 1 . By 4 December 2020 the number of COVID-19 cases (coronavirus disease 2019) throughout the world was estimated at 65 million, while the number of deaths ascribed to COVID-19 had exceeded 1.5 million 2 . In France, by 9 December 2020 the number of confirmed cases was 2,324,216, and the number of deaths ascribed to COVID-19 was 56,648 3 . In the face of this pandemic, different nations have drawn up non-pharmaceutical strategies to limit transmission of the virus 4 . In the modeling developed by Li, the closing of schools and workplaces, the prohibition of public events and of gatherings of more than ten persons, the imposition of home confinement and restrictions on mobility seemed associated with reduced transmission of SARS-CoV-2 4 . That said, these different strategies have major social costs; in France, the first lockdown (17 March to 11 May 2020) led to a decrease in economic activity of 25% 5 . Multiple active principles have been the subject of highly numerous randomized clinical trials in different parts of the world, the common objective being to reduce the transmission and/or severity of COVID-19 6 . As the majority of the world population is not immunized against this emerging infection, vaccination against COVID-19 is shaping up as the long-term solution. For one century, vaccination in general has been considered as the procedure saving a maximum number of lives, and little by little, it has come to represent the optimal solution against infectious diseases 7 . 9 . In March 2020, 10 days after the outset of the initial lockdown, nearly 25% of the 5108 French persons interrogated, a representative sample of the overall population, stated that if a COVID-19 vaccine were to exist, they would probably or certainly refuse to have it administered to them 10 . The initial results of phase I and phase II trials were published in August and November 2020 11, 12 . 15 . The structure has as objectives (i) to set up a nationwide platform for volunteer recruitment, (ii) to establish coordination between investigation centers in the pursuit of industrial and academic trials, (iii) to conduct work on vaccine acceptability (iv) and to assess vaccine tolerance in close conjunction with pharmacovigilance activities. On 30 November 2020, the French health authority (HAS) proposed a five-phase vaccination strategy prioritizing the most fragile individuals in France 16 , and the first vaccinations against COVID-19 are slated to take place in January 2021. The French prime minister has emphasized the central role of general practitioners (GP) with regard to this vaccination. According to a BVA poll, during the first lockdown 93% of his fellow countrymen maintained confidence in their GPs; for 74%, he or she represents their entranceway to the health care system 17 . General practitioners and, more broadly speaking, the caregivers tasked with administering anti-COVID-19 vaccination, will be called upon to answer the questions put forward by healthcare users. In Australia, a letter to GPs aimed at "building vaccine confidence" and "optimizing uptake" 18 has been published. The primary objective of this article is to address and answer questions on vaccine development, vaccination strategy and vaccine acceptability. The second objective is to facilitate shared decisionmaking involving the caregiver and the health care user 19 . From the outset of the COVID-19 pandemic, a race against the clock clicked into gear, the objective being to develop safe and effective vaccines, most often via public-private partnerships 20 . By 2 December 2020, 214 vaccines had been identified by the WHO and were being developed, and 51 of them had entered into a phase of clinical development, that is to say phase I (Figure 1 ) 21 . Usually, as depicted in Figure 1a , the development of a vaccine takes 10 to 15 years 18 23 . What is more, in the midst of an epidemic the vaccine development phases tend to overlap ( Figure 1b ). That said, safety and effectiveness assessment during clinical trials remains in compliance with the usual rules governing clinical vaccine research. Authorization processes have been accelerated and vaccine production anticipated 18 . Concerning production, it can be accelerated in accordance with the vaccine platform procedure, as is the case with RNA messenger (RNAm) platforms. That is why the two vaccines that were the first to have completed Phase III and to have communicated their effectiveness results are RNAm vaccines (Pfizer/BioNTech ® and Moderna ® ). Developed for more than 20 years in the framework of anticancer and anti-infective vaccine approaches, the platforms do not necessitate a step-by-step procedure utilizing cell lines and embryonated eggs, which means that and vaccine production can be exceedingly (sidebar 1) 24 14 . As regards the Moderna ® vaccine, the FDA has made available data from the phase III trial and immunogenicity data on elderly patients (a small population) 12, [26] [27] [28] . At this time, the reported effectiveness of the Pfizer/BioNTech ® vaccine is 95% for the entire population (93.7 % in persons over 55 years of age) 13 . As for the AstraZeneca ® /Oxford vaccine, overall effectiveness neighbors 70%, and is greater in volunteers having received first a ½ dose followed by a full dose than in those having received two full doses; that said, the difference has yet to be wholly elucidated 14 . As concerns Moderna ® , the data transmitted to the FDA show 94.5% effectiveness (CI95 = 86.5 -97.8). In addition to immunity engendering neutralizing antibodies, cellular immunity is apparently triggered by these 3 vaccines 20 . Concerning safety, the reported adverse effects of these vaccines are essentially benign side effects and seem more or less pronounced according to age. With the Pfizer/BioNTech ® vaccine, local "reactogenicity" has appeared after the 2 nd injection among over 60% of volunteers, and general signs (fever, myalgias, asthenia) have been found in 5 to 10% 13 . As regards the AstraZeneca/Oxford ® vaccine, frequent "reactogenicity" (> 60 %) has likewise been reported (pain at the injection site, feverish sensation, muscle pain) 14 . Available safety data are being communicated and monitored, after as well as prior to commercialization 13, 14 . Any caregiver or citizen can make a declaration of an adverse event following vaccination on https://signalement.social-sante.gouv.fr/psig_ihm_utilisateurs/index.html#/accueil. Analysis of the different reports is carried out by a French network composed of 31 regional pharmacovigilance centers, each of which is commissioned to provide expert appraisal of a precise Taking into account these different objectives and constraints, as well as models from other countries, the HAS (French health authority) has proposed a 5-phase schedule (Table 1) with two categories of targets: system users, and their caregivers 16, 18 . During phase 1, which is deemed critical, vaccination priority is given to: residents in establishments As for phase 4, which targets marginalized, precarious and homeless populations, it entails the mobilization not only of general medicine, but also of associational and institutional networks in contact with a problematically accessible public that does not necessarily receive regular medical care. During this phase, the professionals assisting these persons are likewise targeted. Occupational physicians shall be called upon to orient vaccination of workers in enclosed areas (construction, slaughterhouses). General practitioners shall help to identify persons at risk due to confined living quarters. This period may exacerbate existing health care inequalities. Phase 5 extends the vaccination campaign to the entire adult population that has yet to be vaccinated. The herd immunity threshold corresponds to the proportion of individuals who, on account of acquired immunity, can no longer participate in the transmission chain of a pathogenic agent. It depends directly on the reproduction number of the infectious disease (starting with an "index case", the number of infected persons: R0). Given that in SARS-CoV-2 infections, the number ranges from 2 to 3, the herd immunity threshold would be set between 50 and 67% 29 . For comparison's sake, with a RO between 12 and 18, the herd immunity threshold for measles exceeds 90%. Given present-day uncertainty as to post-infection natural immunity by SARS-CoV-2, it remains difficult to determine a target rate for vaccination coverage. That said and most importantly, in order for herd immunity to be acquired it behooves the population to accept vaccination, and in France, vaccine hesitancy is highly pronounced 9 . As regards intentions among the French to be vaccinated against COVID-19, during the first epidemic wave they were estimated at approximately 75% 10, 30 , and then, in June 2020, at 60% 31 . Today, as vaccines are beginning to become available, the intentions collected in the latest public opinion polls range from 40 to 60% 17, 32, 33 . While an overwhelming majority (>85%) of health professionals, particularly physicians and pharmacists, have declared the intention to be vaccinated, among nurses and health assistants only 60 to 65% have concurred 34 . In a context of emerging pathology, the main barriers to vaccination (in order of frequency) are fears concerning vaccine safety, doubts as to vaccine effectiveness, fear of developing COVID-19 due to vaccination, and limited perception of the risks associated with COVID-19 35 . In France, women and youth (under 30 years of age) seem less inclined to be vaccinated than men over 30 years of age 30 . Motivating factors for being vaccinated against COVID-19 have been identified as: strong perception of the potential severity of the infection, and high risk of being infected 30 . The wish to recover a normal life (without restrictive measures) has likewise appeared as a reason for acceptance of vaccination against COVID-19 32 . In a past epidemic situation involving emergence (the 2009 H1N1 flu), the attitudes (vaccine advocacy or hesitancy) of professionals, particularly general practitioners, were of genuine importance in individual decision-making 36 . In today's context of a vaccine developed at "pandemic" speed, it seems legitimate, if only as a basis for discussion with health care users, for caregivers to require reliable, upto-date information on the safety and effectiveness of a given vaccine. Tools specifically designed for use in COVID-19 vaccination decision-making should be rolled out, a key example being the VAC-SI information system, which will facilitate identification of patients for whom vaccination is recommended, ensure tracing of pre-vaccinal consultation and subsequent vaccinations, and report adverse effects. At this stage, however, several issues remain pending, and some of them may render the decision-making process conflictual (sidebar 3). 2. How long does vaccinal immunity last? As of now, it is impossible to answer this question; cohort follow-up studies will be necessary. The legal guardian and the designated support person are likely to be of key importance. The rapid development of vaccines in a health emergency context provides little if any opportunity for perspective. Monitoring subsequent to market authorization will be imperatively necessary. That said, and as is the case with other vaccines, adverse effects usually occur in the short term. The general practitioner is the person who seems most apt to vaccinate his or her patients. However, multi-dose packaging and special conditions for storage seem ill-suited for use by GPs and dispensing pharmacists/chemists. As for mass vaccination at dedicated sites, it could prove detrimental to acceptability. Informing patients on the benefit-risk ratio of COVID-19 vaccinations corresponds to both the evidence-based medicine (EBM) model for therapeutic decision and, more generally, to the shared decision-making model 38 . The two models are closely correlated with the 4 core principles of medical ethics, particularly the non-maleficence (primum non nocere) ensured by vaccine safety, and the beneficence associated with vaccine effectiveness. Clinically relevant and applicable scientific data are delivered to a patient who consults his or her physician in the form of suitable information enabling the person to make an enlightened choice in accordance with the principle of respect for autonomy. 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