: The development of a new vaccine usually consists of a linear sequence of several steps and lasts many years [...]

Baldo V.

Cocchio S.

Fantini M. P.

Reno C.

English

Archivio istituzionale della ricerca - Alma Mater Studiorum Università di Bologna

EditorialSARS-CoV-2/COVID-19 Vaccines: The Promises and theChallenges AheadVincenzo Baldo 1,*,† , Chiara Reno 2,† , Silvia Cocchio 1,† and Maria Pia Fantini 2,†Citation: Baldo, V.; Reno, C.; Cocchio,S.; Fantini, M.P. SARS-CoV-2/COVID-19 Vaccines: The Promisesand the Challenges Ahead. Vaccines2021, 9, 21. https://doi.org/10.3390/vaccines9010021Received: 9 December 2020Accepted: 31 December 2020Published: 4 January 2021Publisher’s Note: MDPI stays neu-tral with regard to jurisdictional clai-ms in published maps and institutio-nal affiliations.Copyright: © 2021 by the authors. Li-censee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms and con-ditions of the Creative Commons At-tribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).1 Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Hygiene and Public Health Unit,University of Padua, 35100 Padua, Italy; silvia.cocchio@unipd.it2 Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum—University of Bologna,40126 Bologna, Italy; chiara.reno@studio.unibo.it (C.R.); mariapia.fantini@unibo.it (M.P.F.)* Correspondence: vincenzo.baldo@unipd.it† All authors contributed to the manuscript equally.The development of a new vaccine usually consists of a linear sequence of several stepsand lasts many years [1]. The sudden outbreak of the SARS-CoV-2/COVID-19 pandemicurged for a quick response and led to an unprecedented effort to produce a vaccine againstthis virus in a very short time, in the context of very limited pre-existing clinical experiencewith any coronavirus vaccine and with multiple steps of development carried out inparallel, with the deployment of different technologies, some of which have never beenused in a licensed vaccine before [2,3]. There is a strong need for vaccines against SARS-CoV-2 as they potentially represent a strong tool to counteract the spread of the virus incombination with non-pharmaceutical interventions that, although essential, are not ableto control it sustainably [4], and in the absence of an effective therapeutic protocol againstCOVID-19. Based on disease and immune response knowledge acquired over the course ofthe pandemic, vaccines should induce high affinity virus-neutralizing antibodies specificfor SARS-CoV-2 to optimally prevent infection and unfavorable events like severe diseaseand death. Namely, these neutralizing antibodies should be directed against a particulardomain (the so-called receptor binding domain—RBD) within the spike (S) protein, whichinteracts with target cell ACE2 receptors [2]. The primary immune mechanism of avoidinginfection is through blocking viral attachment to target cells. Of note, S protein vaccinationmay induce un-wanted antibodies in addition to the neutralizing ones directed against theRBD. Therefore, it is important to construct a vaccine displaying the RBD—or even onlythe RIS (Receptor Interaction Site) conformation instead of the whole S protein—as otherantibodies might sustain the risk of disease enhancement as demonstrated in the past forsome inactivated coronavirus vaccines in animal models [2].The herd immunity threshold for SARS-CoV-2 has been calculated to range between50% and 67%, with the assumption of no population immunity, in the absence of anyinterventions and considering all individuals are equally susceptible and infectious [5].Certainly, the durability of immune memory is key in sustaining herd immunity [5].Seroprevalence studies carried out worldwide suggest that less of 10% of the includedpopulation has been infected, highlighting that the vast majority of individuals are stillsusceptible to the infection [6].The different types of vaccines under development include inactivated or weakenedvirus (virus vaccines), protein subunit or virus-like particles (protein-based vaccines) andreplicating or non-replicating viral vector vaccines. [3,7]. However, the real novelty isrepresented by nucleic acid vaccines (DNA- or RNA-based) that are designed to insertgenetic instructions, mainly for virus spike’s pieces production, into the human cell; sofar this kind of technology has not been used in approved vaccines [3]. This methodshows great potential because no culture or fermentation is required, allowing for a fastproduction [1].Vaccines 2021, 9, 21. https://doi.org/10.3390/vaccines9010021 https://www.mdpi.com/journal/vaccinesVaccines 2021, 9, 21 2 of 4As of 23 December 2020, after more than eleven months since the isolation of thestrain of the new coronavirus, there are 287 vaccines candidates, of which 224 are atthe pre-clinical stage of development, sixty-three are being tested in clinical studies onhumans and fifteen reached phase three of development and are being tested for efficacyon a large scale [8]. Moreover, at present, the European Medicines Agency (EMA) isconsidering four COVID-19 vaccines through the “rolling review” procedure, a regulatorytool to speed up the assessment of medicines or vaccines during a public health emergencyand consisting of reviewing data as they become available, before the submission of theformal application for marketing authorisation [4]. In particular, two candidate mRNA-based vaccines include BNT162b2 and mRNA-1273, and two non-replicating viral vectorvaccines include ChAdOx1 nCoV-19 and Ad26.COV2.S [7,8]. Currently, BNT162b2 andmRNA-1273 vaccines have been approved in several countries. On 2 December 2020,the United Kingdom granted emergency authorization to the BNT162b2 vaccine, thusbeing the first Western country to give an approval to a coronavirus vaccine [9], followedsome days later by the Food and Drug Administration (FDA) in the US [10]. Shortly after,on 21 December 2020, the BNT162b2 vaccine was authorised across the EU followingEMA’s recommendation for a conditional marketing authorization [11]. As regards themRNA-1273 vaccine, it received emergency use authorization by the FDA on 18 December2020 [12]. Considering this candidate and the European context, the assessment by theEMA of the marketing authorization application is ongoing and at the beginning of January2021 a meeting will take place to possibly conclude it [13].To emphasize the importance of the availability of the COVID-19 vaccine, the EuropeanCommission has diversified vaccine portfolios and concluded six different contracts withpharmaceutical companies. These vaccine candidates are in an advanced phase of clinicaltrials and once the vaccines have been proven to be safe and effective, they will be quicklyspread. Furthermore, the different types of development of vaccine platforms will ensurethe possibility of different strategies [14–16]. While the development and availability ofvaccines can be accelerated, standards for vaccine quality, safety and efficacy remains afundamental prerequisite for marketing authorisation [4]. In addition, as highlighted bythe technical report of the European Centre for Disease Prevention and Control (ECDC,26 October 2020), a sustained monitoring programme based on post-marketing studies onthe impact, effectiveness and safety of deployed vaccines, as well as routine reporting ofadverse events following immunisation, will be crucial to inform policy decisions and toprovide timely evidence [17].Several official documents provide indications on potential priority groups to considerwhen designing and implementing vaccination programmes [4,17] and a survey carried outby the ECDC on vaccination strategies and vaccine deployment plans in the EU/EEA andUK highlighted that, as of 30 November 2020, nine countries have already published interimrecommendations for priority groups [18]. The need for a flexible approach, sensitive tolocal conditions is essential; strategies should adapt to emerging evidence, epidemiologicalsituations, vaccine delivery system capacities and the availability of vaccines themselves,among others. Surely, the starting point for planning is the objective of the vaccinationprogramme: should vaccination prevent death and alleviate disease burden, or shouldit counteract the spread of the virus? To answer this question both the target populationand the type of vaccine being used, considering the different endpoints that differenttypes of vaccines can have, need to be taken into account. If the primary aim is to reduceCOVID-19-related disease and deaths, while at the same time reducing the strain onhealthcare systems, vulnerable people at higher risk to severe or fatal outcomes becauseof age or underlying conditions should be prioritized (older age, hypertension, diabetes,cardiovascular disease, chronic respiratory disease, chronic kidney disease and obesity,etc.), together with healthcare workers and essential workers with a significant risk ofexposure. As long as the availability of COVID-19 vaccines is limited, categories at risk ofsevere disease should be privileged even among healthcare workers and essential workerswith a significant risk of exposure.Vaccines 2021, 9, 21 3 of 4Later on, assuming greater availability of COVID-19 vaccines, vaccination strategiescould adapt and also include younger individuals in order to address asymptomatictransmission, that largely contributes to the spread of SARS-CoV-2 and that is most commonin younger age segments, therefore limiting the circulation of the virus and indirectlyproviding protection to the most vulnerable individuals. However, in this second scenarioit must be proven that vaccines prevent not only symptomatic severe disease but alsoinfection and its transmission. Moreover, the safety profile should be highly rigorousbecause of the low risk of young people in case of infection and their longer life expectancy.COVID-19 vaccination strategies should be carefully planned and should account forlimited availability, especially early after marketing authorization, posing a great challengein terms of both prioritization and organization. Of capital importance, the issue to beaddressed is COVID-19 vaccine distribution and allocation, which is directly related toethical considerations regarding equitable worldwide access once the vaccines will beavailable [19]. Defining risk groups to be taken into account for vaccination access and theirprioritization is of great importance, in addition to keeping in mind that socio-economicconditions highly contribute to the burden of this disease; indeed, COVID-19 could bedefined as a syndemic, rather than a pandemic, accounting for social and environmentalfactors that could have a critical role in promoting and enhancing the disease [20].At present, there are no definite estimates on the number of doses that will be poten-tially available and on the timing of supply. In order to design and implement a feasibleand efficient vaccination programme, delivery aspects need to be properly taken intoaccount and could include type of settings different from the usual ones, according to thetarget population [17]. Vaccination services should be easily accessible and should also beadequately equipped with sufficient resources in terms of personal protective equipment(PPE) [4]. Furthermore, vaccine storage issues (such as considerations regarding extremelylow temperatures some vaccines must be kept at) and the number of required doses perperson, thus, the possible need for follow-up will play a fundamental role in the logistics;dedicated personnel should be adequately trained and prepared for a possibly high loadvaccination campaign [17]. On the other side, nonetheless, targeted, tailored and transpar-ent communication campaigns are critical in building trust and ensuring that the adequatevaccination coverage is reached, counteracting misinformation and vaccine hesitancy.The great attention on the COVID-19 vaccine should not distract the focus from othervaccinations. For example, an adequate coverage against flu is crucial to limit the spreadof this respiratory virus, to reduce the impact on healthcare systems and to facilitatedifferential diagnosis with COVID-19 in specific segments of the population at higher riskof symptomatic and severe disease.In conclusion, before the introduction of one or more COVID-19 vaccines, it is ofhigh importance that policy makers, professional and scientific societies and civil societyorganizations are prepared with vaccine delivery infrastructure, assessing different scenar-ios and the impact of alternative vaccination strategies. Lessons learned from the H1N1pandemic should also be considered. In synthesis, key components for successful policyand vaccination programmes include timely, flexible and evidence-based decisions, robustsurveillance systems for COVID-19 disease and monitoring of adverse events followingimmunization, communication plans and equitable access to vaccination. The promise ofthe new COVID-19 vaccine is great, but there are further challenges yet to be overcome.Funding: This research received no external funding.Conflicts of Interest: The authors declare no conflict of interest.References1. Lurie, N.; Saville, M.; Hatchett, R.; Halton, J. Developing Covid-19 Vaccines at Pandemic Speed. N. Engl. J. Med. 2020, 382,1969–1973. [CrossRef] [PubMed]2. Speiser, D.E.; Bachmann, M.F. COVID-19: Mechanisms of Vaccination and Immunity. Vaccines 2020, 8, 404. [CrossRef] [PubMed]3. Callaway, E. The race for coronavirus vaccines: A graphical guide. Nat. Cell Biol. 2020, 580, 576–577. [CrossRef] [PubMed]Vaccines 2021, 9, 21 4 of 44. European Commission. Available online: https://ec.europa.eu/health/sites/health/files/vaccination/docs/2020_strategies_deployment_en.pdf (accessed on 30 November 2020).5. Omer, S.B.; Yildirim, I.; Forman, H.P. Herd Immunity and Implications for SARS-CoV-2 Control. JAMA 2020, 324, 2095. [CrossRef][PubMed]6. World Health Organization. Available online: https://www.who.int/news-room/q-a-detail/herd-immunity-lockdowns-and-covid-19 (accessed on 30 November 2020).7. Jain, S.; Batra, H.; Yadav, P.; Chand, S. COVID-19 Vaccines Currently under Preclinical and Clinical Studies, and AssociatedAntiviral Immune Response. Vaccines 2020, 8, 649. [CrossRef] [PubMed]8. COVID-19 Vaccine Tracker. Available online: https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/ (accessed on 23 Decem-ber 2020).9. GOV.UK. Available online: https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19 (accessed on 23 December 2020).10. Food and Drug Administration. Available online: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/pfizer-biontech-covid-19-vaccine (accessed on 23 December 2020).11. European Medicines Agency. Available online: https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu (accessed on 23 December 2020).12. Food and Drug Administration. Available online: https://www.fda.gov/news-events/press-announcements/fda-takes-additional-action-fight-against-covid-19-issuing-emergency-use-authorization-second-covid (accessed on 23 December 2020).13. European Medicines Agency. Available online: https://www.ema.europa.eu/en/news/update-assessment-marketing-authorisation-application-modernas-mrna-1273-covid-19-vaccine (accessed on 23 December 2020).14. European Medicines Agency. Available online: https://www.ema.europa.eu/en/news/ema-starts-first-rolling-review-covid-19-vaccine-eu (accessed on 30 November 2020).15. European Medicines Agency. Available online: https://www.ema.europa.eu/en/news/ema-starts-second-rolling-review-covid-19-vaccine (accessed on 30 November 2020).16. European Commission. Available online: https://ec.europa.eu/info/live-work-travel-eu/coronavirus-response/public-health_en (accessed on 30 November 2020).17. European Centre for Disease Prevention and Control. Key Aspects Regarding the Introduction and Prioritisation of COVID-19Vaccination in the EU/EEA and the UK; ECDC: Stockholm, Sweden, 2020.18. European Centre for Disease Prevention and Control. Overview of COVID-19 Vaccination Strategies and Vaccine Deployment Plans inthe EU/EEA and the UK; ECDC: Stockholm, Sweden, 2020.19. Persad, G.; Peek, M.E.; Emanuel, E.J. Fairly Prioritizing Groups for Access to COVID-19 Vaccines. JAMA 2020. [CrossRef][PubMed]20. Singer, M.; Bulled, N.; Ostrach, B.; Mendenhall, E. Syndemics and the biosocial conception of health. Lancet 2017, 389, 941–950.[CrossRef]

SARS-CoV-2/COVID-19 vaccines: The promises and the challenges ahead

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SARS-CoV-2/COVID-19 vaccines: The promises and the challenges ahead

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