1. Introduction

On 27 January 2020, vaccination campaigns against severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) officially started across Europe. Symbolically, this day represents a great achievement for science occurring approximately one year after the reporting to the World Health Organization (WHO) of a cluster of pneumonia of unknown origin in Wuhan City, Hubei Province of China ^[1]. The development and production of vaccines against SARS-CoV-2 took place at an impressive speed, considering, for example, that the first US trial began 66 days later the online publication of the viral RNA sequence ^[2]. A major innovation consists in the use of technologies, besides the more traditional ones, that have never been used in a licensed vaccine before, such as mRNA platforms ^[3]. While the SARS-CoV-2 pandemic continues to strike and collect its death toll throughout the globe, the availability of safe and effective vaccines can truly represent a precious and much-needed tool to mitigate its effect, together with non-pharmaceutical interventions, and, in particular, to offer early protection to some vulnerable strata of the population (i.e., the elderly). From a global perspective, in the long term, effective vaccine mass utilization will also be capable of reducing the social and economic burden of the pandemic and paving the way for an acceptable exit strategy from the current crisis.

When developing vaccination strategies, it is crucial to consider how the different segments of the population are affected by the infection. Older population groups have proved to be highly susceptible to this infection and to severe disease, while children seem to be less affected by the epidemic ^[4][5][6]. Nonetheless, young people, mainly asymptomatic or paucisymptomatic, may contribute to the spread of the infection, given their social habits and school attendance. Vaccination of older people is the optimal age-based strategy to reduce the burden of the disease and the strain on healthcare systems, while vaccination of younger adults could reduce the incidence of the infection.

Vaccination programs should optimize vaccine allocation maximizing public health benefit and taking into account that in the next months, the demand for vaccines will exceed supply ^[6][7]. Moreover, the rapid scale-up of vaccination campaigns, besides the basic key principle of equitable access, also requires considering several other aspects, such as the whole delivery infrastructure, logistic coordination and surveillance of adverse events after immunization ^[7].

Surely, as the success of the vaccination deployment greatly relies on the uptake by the targeted population, efforts in transparent and effective communication campaigns are of paramount importance to counteract misinformation and vaccine hesitancy and to build trust in the population to ensure that adequate vaccination coverage is reached ^[7].

Since the outbreak of the pandemic, we have been overwhelmed by information from different channels, from the more traditional ones to social media, and the same is happening with vaccines. These multiple sources of information have the great potential to influence public opinion, therefore having an impact on vaccination acceptance and eventually on vaccine hesitancy ^[8].

2. Type of Anti-COVID-19 Vaccines, Their Efficacy and Safety, and Vaccination Strategies

The public health emergency has accelerated both the development and the approval of COVID-19 vaccines. The European Medicines Agency (EMA) put in place rapid review procedures and a dedicated expert task force to review applications as rapidly as possible while ensuring at the same time robust scientific opinions ^[9].

One year after the outbreak of the pandemic, as of 31 January 2021, the vaccine candidates worldwide are 292, of which 70 in clinical testing ^[10]. Three anti-COVID-19 vaccines have been authorized for use in the EU following recommendations by the EMA ^[11]: BioNTech-Pfizer (mRNA), Moderna (mRNA) and AstraZeneca (nonreplicative viral vector). Moreover, three contracts have been concluded to purchase a vaccine once proven safe and effective: Sanofi-GSK (protein subunit), Johnson and Johnson (nonreplicative viral vectorl) and CureVac (mRNA). In addition, the European Commission has concluded exploratory talks with the European companies Novavax (protein subunit) and Valneva (inactivated virus).

Besides the extraordinary timing that led to the development and authorization of vaccines, a point of great novelty is the use of technologies that have never been used in a licensed vaccine before ^[3], on which the three vaccines authorized for use in the EU are based. Vaccines by BioNTech-Pfizer and Moderna are mRNA-based, a type of technology long-studied and which has always been considered really promising ^[12][13]. AstraZeneca vaccine relies on a nonreplicative recombinant chimpanzee adenovirus-based platform. All these three vaccines require two doses while a point of difference is represented by storage conditions; the AstraZeneca vaccine does not require low-temperature storage, and this is a key element for logistical considerations when planning a mass vaccination campaign.

Both BioNTech-Pfizer and Moderna vaccines showed high efficacy in terms of reduction of symptomatic cases, 95% and 94.1%, respectively ^[14][15]. However, a major question that has not yet been answered remains, namely whether the vaccines protect against asymptomatic infection and transmission to susceptible people.

The AstraZeneca vaccine demonstrated around 60% efficacy in reducing the number of symptomatic COVID-19 cases in vaccinated people across four clinical studies involving around 24,000 individuals ^[16]. Of note, participants were between 18 and 55 years old. Therefore to date, it is not certain how well this vaccine could work in older participants. Based on these considerations, in Italy, the regulatory agency (AIFA) recommended this type of vaccine for people aged between 18 and 55, while mRNA vaccines should be prioritized for older and fragile people ^[17]. However, recently, WHO recommended this type of vaccine also for people aged 65 or older ^[18].

As regards safety, the reported side effects for all three vaccines were usually mild or moderate. Allergic reactions after the first dose of an mRNA vaccine have been reported, and scientists suspect that they may be due to a specific compound, polyethylene glycol (PEG), never used before in an approved vaccine, but further studies are necessary to confirm or refute this hypothesis ^[19]. Postmarketing studies are needed to monitor potential side effects in the long term and taking into account that several segments of the population were not recruited in efficacy and safety trials, such as pregnant women, severely immunocompromised individuals, children and adolescents.

Given the availability of these new vaccines, roughly a month since the official beginning of the vaccination campaign, two major issues are now emerging.

First, uncertainty on the number of doses and their arrival time already exists, leading to organizational problems and changes in the vaccine campaign strategic plans.

Second, new variants of the virus have been identified during the past months. The risk assessment by the European Centre for Disease Prevention and Control (ECDC) has been increased to high/very high in relation to the introduction and community spread of three new variants that have been identified in the UK, South Africa and Brazil ^[20]. Therefore, an open question that urgently needs an answer is whether these new variants will escape recognition by the immunity induced by vaccines ^[21]. What is known so far is that variant B.1.1.7. (the often so-called “UK strain”) has been neutralized in vitro by serum samples of recipients of the Pfizer-BioNTech and Moderna mRNA vaccines ^[21]. On the other side, variant B.1.351 (identified in South Africa) and the close relative identified in Brazil have more alarming sequence changes, thus raising serious concerns about vaccine efficacy ^[21]. However, the strong response stimulated by mRNA vaccines in terms of neutralizing antibodies could be enough to avoid a significant loss of effectiveness, while other types of vaccines that induce lower levels of these neutralizing antibodies could be less effective ^[21]. It is therefore highly important to put in place a sequencing surveillance system to monitor the emergence of new variants and to evaluate the effectiveness of vaccines thoroughly and continuously, trying in the meantime to reach adequate levels of vaccination as soon as possible. Of note, researchers are considering redesigning vaccines against SARS-CoV-2, and some coronavirus vaccine makers are already taking into account updating their vaccines to counter these new strains ^[22]. Thanks to validated platforms long studied before the pandemic, this process could take place relatively rapidly, potentially following the updated model of seasonal flu vaccines.